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In vitro studies of the renin-angiotensin system in human adipose tissue/adipocytes and possible relationship to SARS-CoV-2: a scoping review

In vitro studies of the renin-angiotensin system in human adipose tissue/adipocytes and possible... ADIPOCYTE 2023, VOL. 12, NO. 1, 2194034 https://doi.org/10.1080/21623945.2023.2194034 REVIEW In vitro studies of the renin-angiotensin system in human adipose tissue/ adipocytes and possible relationship to SARS-CoV-2: a scoping review a a,b,c a,b,c,d Ryan Ting , Heidi Dutton , and Alexander Sorisky a b c Faculty of Medicine, University of Ottawa, Ottawa, Canada; Department of Medicine, University of Ottawa, Ottawa, Canada; The Ottawa Hospital/Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada ABSTRACT ARTICLE HISTORY The renin-angiotensin system (RAS) operates within adipose tissue. Obesity-related changes can Received 27 September 2022 affect adipose RAS, predisposing to hypertension, type 2 diabetes, and possibly severe COVID-19. Revised 20 December 2022 Accepted 2 January 2023 We evaluated the in vitro research on human adipose RAS and identified gaps in the literature. Medline (Ovid), Embase (Ovid), Web of Science, Scopus, and 1findr were searched to identify KEYWORDS relevant studies. Fifty primary studies met our inclusion criteria for analysis. Expression of RAS Renin-angiotensin system; components (n = 14), role in differentiation (n = 14), association with inflammation (n = 15) or adipose tissue; human; blood pressure (n = 7) were investigated. We found (1) obesity-related changes in RAS were in vitro studies frequently studied (30%); (2) an upswing of articles investigating adipose ACE-2 expression since the COVID-19 pandemic; (3) a paucity of papers on AT2R and Ang (1–7)/MasR which counterbalance Ang II/ART1; (4) weight loss lowered adipose ACE-2 mRNA expression; and (5) angiotensin receptor blockers (ARBs) reduced deleterious effects of angiotensin II. Overall, these studies link Ang II/ATR1 signalling to impaired adipogenesis and a pro-inflammatory dysfunctional adipose tissue, with ATR1 blockade limiting these responses. ACE-2 may mitigate Ang II effects by converting it to Ang(1–7) which binds MasR. More work is needed to understand adipose RAS in various pathologic states such as obesity and COVID-19 infection.T. 1. Introduction The renin-angiotensin system (RAS) is involved in the peptides that act locally or enter the circulation to regulation of blood pressure, electrolyte balance, exert distant effects. Adipocytes produce and secrete inflammation, and tissue remodelling. [1] all of the described RAS components [4]. Angiotensinogen (AGT) is released from the liver and Adipose tissue is a multi-depot organ and plays is cleaved to form angiotensin I (Ang I) by renin a role in energy regulation and inflammation/immu- secreted from the kidneys. Ang I is then processed by nity. RAS in adipose tissue plays an important role in angiotensin converting enzyme-1 (ACE-1) to form adipogenesis as well as in lipid/glucose metabolism and angiotensin II (Ang II). Other non-RAS enzymes such inflammation [5]. Obesity-associated pro-inflammatory as cathepsin D can also cleave AGT to produce Ang II and oxidative stress results from adipocyte hypertrophy [2]. Ang II interacts with angiotensin type 1 receptors and associated cellular hypoxia [6]. This increases (AT1R) and angiotensin type 2 receptors (AT2R) to macrophage infiltration into adipose tissue promoting exert its physiological effects. This includes vasocon- expression of inflammatory mediators and dysregula- striction of vascular smooth muscle cells and aldoster- tion of adipokines such Ang II. An increase in Ang II one release from the adrenal cortex, leading to sodium has been suggested to contribute to obesity-associated and water retention and an increase in blood pressure hypertension and insulin resistance [5]. [2]. Ang II is cleaved by angiotensin converting Adipose RAS may potentially contribute to the enzyme-2 (ACE-2) to Ang (1–7) which interacts with body’s response to viral infections. In 2003, a global Mas receptors (MasR) to counteract the vasoconstric- outbreak of severe respiratory syndrome caused by tor-promoting effects of Ang II [3]. Several tissues coronavirus SARS-CoV-1 resulted in 916 deaths [7]. possess their own RAS and generate angiotensin From 24 January 2020 to 30 July 2021, the global CONTACT Alexander Sorisky asorisky@ohri.ca Chronic Disease Program, OHRI, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada Supplemental data for this article can be accessed online at https://doi.org/10.1080/21623945.2023.2194034 © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 R. TING ET AL. pandemic of COVID-19 caused by coronavirus SARS- 24 June 2020: MEDLINE, EMBASE, PubMed, Web of CoV-2 has resulted in 4,248,387 deaths [8]. The SARS- Science, Scopus, and 1findr. The search strategies were CoV-1 and SARS-CoV-2 viruses selectively bind to drafted in consultation with an information specialist ACE-2 to infect human cells and may reduce ACE-2 (KF) and further refined through team discussion with locally or systemically [9]. Recently, SARS-CoV-2 RNA all authors. A pretested combination of keywords and has been detected in adipocytes [10]. The reduction of MESH terms were used based upon the identified core ACE-2 could disrupt Ang II/AT1R and Ang (1–7)/ concepts of the research question: (1) adipose tissue/ MasR homoeostasis [11]. Increased Ang II levels have cells; (2) renin-angiotensin system; (3) in vitro. been associated with vasoconstriction, inflammation, A detailed search strategy for MEDLINE (Ovid) is cell proliferation, hypertrophy, fibrosis, and tissue shown in Supporting Information S1. Additional remodelling [12]. Individuals with obesity are at high sources of information included reference lists from risk for severe COVID-19 infections, and it has been retrieved papers [16]. suggested higher levels of ACE-2 in adipose cells may We also searched PubMed on 30 July 2021 using the lead to this tissue acting as a reservoir for viral spread terms ‘human’, ‘adipose’, and ‘ACE-2’ to identify the within an individual [9]. Therefore, reviewing what is ongoing activity of ACE-2 publications after the first known about the human cellular function of adipose search was completed. RAS is timely and pertinent. We undertook a scoping review to provide 2.4. Study selection a preliminary assessment of this broad and complex emerging topic. The primary objective was to provide Eligibility criteria were established based on research an overview of in vitro research investigating the func- questions and pretested in PubMed. Primary research tion of RAS in adipose tissue/adipocytes derived from articles written in English that fulfiled the following human cell lines or human adipose tissue, and its criteria were included in the analysis: (i) a component possible association with SARS-CoV-2. Our secondary of the renin-angiotensin system was investigated; (ii) at objective is to identify uncertainties or gaps in the least one indicator of cellular expression of RAS in existing literature, providing a framework for future adipose tissue/adipocytes was identified; (iii) studies research initiatives. were performed with human adipose/adipocytes or human cell lines in vitro; (4) studies were related to adipose tissue or adipocyte function. We did not 2. Methods include animal cell studies in this defined scoping review, as they are not as relevant and immediate as 2.1. Methodological approach human cell studies are to the understanding of clinical The review process was based on the methodological disease states. framework proposed by Arksey and O’Malley [13]. The Studies excluded from this study were as follows: (i) review was conducted in accordance with the Preferred manual duplicates (ii) review articles and meta-analysis; Reporting Items for Systematic reviews and Meta- (iii) studies for which the full-text article did not exist Analyses extension for Scoping Reviews (PRISMA- such as a conference/abstract; (iv) editorials/commen- ScR) checklist guidelines [14,15]. Registration for scop- taries; (v) in vivo human studies that did not include ing reviews on PROSPERO (the NIH international isolated adipose tissue/adipocytes or human adipose prospective register of systematic reviews) was not cell lines; (vi) studies performed with other human available at the time this article was prepared. cells that did not include adipose tissue/adipocytes; (vii) in vitro studies which did not examine the effect of RAS in human adipose tissue/adipocytes; (viii) 2.2. Research question and key concepts in vitro studies involving adipose tissue/adipocytes What are the extent and nature of in vitro research from animal-derived tissue (transgenic animals), cells, investigating the renin-angiotensin system in human and cell lines; (ix) studies reported in languages for adipose tissue/adipocytes? What is the possible associa- which no English language translation was available. tion of human adipose RAS with SARS-CoV-2? 2.5. Screening 2.3. Database search All the retrieved records from the databases and hand- To identify relevant documents, the following biblio- searches were imported in Zotero reference manage- graphic databases were searched from inception to ment database (version 5.0 Corporation for Digital ADIPOCYTE 3 Scholarship, Roy Rosenzweig Center for History and 3.2. Study characteristics New Media, George Mason University, Fairfax, VA, The publication period of the 50 eligible studies ranged USA). The records were then converted into a RIS from 2001 to 2021. Of these, 14 studies investigated format for import into Covidence systematic review expression of RAS components, 14 studies investigated software, Veritas Health Innovation, Melbourne, RAS and differentiation, 15 studies investigated RAS Australia (available at www.covidence.org) which was and inflammation, and 7 studies investigated RAS and used for screening. In order to minimize bias, titles and blood pressure. Tables 1–4 contain specific details of abstracts of studies identified by the systematic search each study such as those related to age, gender, depot of were screened for relevance by two independent inves- adipose tissue and country. tigators, AS and RT. Relevant articles identified through the screen were reviewed for complete assess- 3.2.1. Expression of RAS components ment of eligibility criteria. Discrepancies were resolved Assessing ACE-2 expression in adipose tissue has through discussion and consensus. A third reviewer, grown in interest recently, given its possible role as HD, was available to resolve any conflicts. a SAR-CoV-2 viral receptor with respect to obesity and susceptibility to COVID-19 infection. A variety of adipose depots were examined. Four articles detected 2.6. Data extraction high ACE-2 gene expression in adipose tissue relative to other tissue types [17–20] (Table 1). The other four Prior to the search, a data extraction form was designed to articles examined ACE-2 mRNA expression in relation facilitate interpretation, comparison, and synthesis of the to BMI [21–24]. Kristem et al. used GEO datasets to findings from the included studies. Pretesting of the data measure ACE-2 gene expression in subcutaneous white extraction form was performed by RT on five papers, adipose tissue (SAT) from patients with severe obesity, which then led to further refinement of the form after before and after Roux-en-Y gastric bypass (RYGB); discussion with the other authors. RT conducted the results showed RYGB was associated with lower ACE- extraction. AS verified the data extraction to ensure accu- 2 mRNA expression [21]. Similarly, Li, L et al. observed racy and reproducibility. The final version of the form that weight loss was associated with a decline in SAT included: authors, publication year, paper title, journal, ACE-2 mRNA [22]. Favre et al. noted that expression country of senior/corresponding author, purpose, study of ACE-2 mRNA paralleled BMI in visceral adipose population, cell type(s) isolated/source of tissues, compo- tissue (VAT) from overweight patients, and has been nents of RAS studied, methodology (study design), the only publication to correlate that in patients with or experimental treatments, key findings, and sponsorship. without COVID-19 infection [23]. Couselo-Seijas et al. found ACE-2 and ADAM17 (its cleavage enzyme) mRNA expression levels were higher in epicardial adi- 3. Results pose tissue (EAT) from patients with type 2 diabetes mellitus and ACE-2 was highest in patients with obesity 3.1. Study selection and diabetes [24]. Desterke et al. found ACE-2 mRNA Our initial search strategy conducted on 24 June 2020 was highly expressed in adipose-derived mesenchymal identified 3232 articles. Removal of duplicates by stem cells (MSC) [25]. deLigt et al. studies participants Covidence resulted in 1390 unique articles. After who received either valsartan or placebo for 26 weeks screening titles and abstracts for relevance, 62 studies [26]. Abdominal SAT biopsies were collected before were eligible for full-text review. Of these articles, 26 and after 26 weeks of treatment. There were no signifi- were excluded for the following reasons: not conducted cant differences in ACE-2, AGT, ACE-1 and AT1R in human adipose tissue/cells (n = 11), full text not mRNA expression in SAT between the valsartan or available (n = 9), manual duplicates (n = 5), no discus- placebo groups. sion section (n = 1). This left 36 studies to review. Four of the 14 articles examined the expression of RAS A PubMed search was conducted on 30 July 2021 to components other than ACE-2 [27–30]. Mackay et al. capture articles for ACE-2 published after our initial demonstrated that AGT mRNA expression was similar in database search. Additional 14 studies were retrieved. medullary adipocytes, human mesenchymal stem cell- Therefore, 50 studies were included in this scoping derived adipocytes and subcutaneous adipocytes [27]. review [17–66] (Figure 1). Fain et al. observed that most of the in vitro release of 4 R. TING ET AL. Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram. ACE-1 from adipose tissue was by stromal non-fat cells AT1R mRNA was greater in adipocytes than preadipo- and more ACE-1 was released by omental adipose tissue cytes, whereas renin receptor mRNA expression was (OAT) from patients with class III obesity > 40 kg/m equal between adipocytes and preadipocytes, and the (mean BMI 46 kg/m ) versus patients with class I obesity expression of ACE-1 mRNA was lower in adipocytes 2 2 BMI 30–35 kg/m (mean BMI 32.9 kg/m ) [28]. Fain than preadipocytes. Archard et al. reported (pro)renin et al. compared mRNA expression from adipocytes ver- receptors were synthesized in the stromal portion of sus preadipocytes for AGT, renin receptor, AT1R and human adipose tissue (SAT and OAT) in preadipocytes ACE-1 in OAT [29]. The expression of AGT mRNA and and non-preadipocyte cells [30]. Renin binding to ADIPOCYTE 5 Table 1. Expression of RAS components in human adipose tissue in vitro studies (N = 14). RAS Component(s) Reference Study population & Country of Corresponding Author Cell type(s) isolated/Source of tissues studied Key Findings Archard Females 18–55 yrs.: Stromal preadipocytes from biopsies AGT, and RenR was localized in the cell periphery. et al. BMI 21.0 ± 2.2 (n = 14); BMI 37.9 ± 5.2 (n = 17) of abdominal SAT and omental VAT. Renin receptor Renin binding to RenR of preadipocyte cells in vitro stimulated 2007 [30] (France) (RenR) intracellular-signalling pathways and potentiated AGT to Ang I generation. RenR expression was higher in VAT. Couselo- 36 patients who underwent open-heart surgery. Age 70 ± 0.8 yrs. Females Epicardial fat (EAT) and SAT biopsies; ACE-1, and Similar levels of ACE-1 in EAT and SAT. Seijas (n = 11); Male (n = 25); Obese and non-obese BMI 30 ± 0.95; diabetic and Stromal vascular cells (n = 8). ACE-2 EAT expressed higher levels of ACE-2 and lower ADAM17 mRNA et al. non-diabetic patients. than SAT. 2021 [24] (Spain) EAT and SAT from cardiac patients with obesity and T2DM had the highest levels of ACE-2 mRNA. Diabetic patients treated with ARBs had higher ACE-2 mRNA levels than diabetic patients not treated with ARBs. de Ligt et al. Impaired glucose metabolism. Abdominal SAT biopsy. AGT, AT1R, Expression of AGT, ACE-1, ACE-2 and AT1R mRNA in group 2021 [26] BMI 31 ± 0.8 (n = 36) ACE-1, and treated for 26 weeks with valsartan was not significantly dif- (Netherlands) ACE-2 ferent from the placebo group. Desterke Transcriptome datasets from Gene Expression Omnibus (GEO) website. Human mesenchymal stem cells ACE-2 ACE-2 mRNA was highly expressed in adult bone marrow, et al. (France) (hMSC). adipose tissue, and umbilical cord-derived hMSC. 2021 [25] Fain et al. Female avg. 39 yrs. Explants of abdominal SAT, and ACE-1 The majority of the in vitro release of ACE-1 was from non-fat 2007 [28] Obese: omental VAT. (Non-fat cell and cells. Mean BMI 32.9 (n = 10) adipocyte fractions) Higher levels of ACE-1 are released by adipose tissue from Morbidly obese: subjects with morbid obesity. Mean BMI 46 (n = 12). Higher levels of ACE-1 released by omental VAT versus SAT (USA) explants. Fain et al. Female avg. 40 yrs. Stromovascular portion of omental AGT, AT1R, Adipocyte versus non-adipocyte mRNA: AGT is higher in adi- 2008 [29] Morbidly obese avg. VAT. ACE-1 and pocytes and RenR lower in adipocytes. BMI 46 RenR Adipocyte vs. preadipocyte mRNA: AGT & AT1R higher in adipo- (USA) cytes; RenR same; ACE-1 lower in adipocytes. Favre et al. Non-obese patients with and without COVID-19. VAT and SAT ACE-2 Positive correlation between ACE2 mRNA and BMI in VAT, but 2021 [23] (France) not SAT. Higher ACE2 with COVID-19 ACE-2 was not related to age and sex. Han et al. RNAseq transcriptome and sex data from the genotype-tissue expression Human tissues ACE-2 ACE-2 mRNA levels were highest in the small intestines. 2020 [17] (GTEx) and the Cancer Genome Atlas (TCGA). ACE-2 mRNA levels were high in salivary glands, testicular, kid- (China) ney, heart, thyroid and adipose tissue. No significant sexual differences in ACE2 gene expression. Kerslake Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), and Human tissue ACE-2 ACE-2 mRNA was expressed in adipose tissue. et al. GEPIA (http://gepia.cancer). 2020 [18] (United Kingdom) (Continued ) 6 R. TING ET AL. Table 1. (Continued). RAS Component(s) Reference Study population & Country of Corresponding Author Cell type(s) isolated/Source of tissues studied Key Findings Kristem Gene Expression Omnibus (GEO) Data Sets. SAT pre- and post- Roux-en-Y gastric ACE-2 ● After RYGB, mRNA expression of ACE-2 in SAT decreased. et al. Females avg. 47 years: Obese (n = 16); non-obese (n = 16) bypass (RYGB) ACE-2 in SAT was lower in post-RYGB patients vs non-obese 2021 [21] (USA) matched controls. Li, L et al. Age>18 yrs. SAT biopsy ACE-2 No difference in ACE-2 mRNA expression for males and females 2020 [22] Obese (n = 156); and differences in age. Female (n = 120); ACE-2 mRNA expression was reduced in insulin-resistant subjects. Male (n = 36) ACE-2 mRNA expression was correlated with adipose leptin pro- (Germany) duction. ACE-2 mRNA expression was lower after BMI reduction and improved insulin sensitivity. Li, M et al. GTEx datasets (RSEM normalized) from UCSC Xena project, TCGA datasets Human tissues ACE-2 ACE-2 mRNA expression levels in adipose tissue were high in 2020 [19] from Genomic Data Commons Data Portal. comparison to other tissue types. (China) No difference in ACE2 mRNA expression between males and females or between younger and older persons in any tissues. Liu, et al. GTEx database; COVID-19 host genetics initiative 2020. Human tissues ACE-2 ACE-2 mRNA was found in adipose tissue. 2021 [20] (Sweden) ● ● ● Mackay Donors aged 22–27 yrs. hMSC and medullary adipocytes. Medullary adipocytes and hMSC AGT Medullary, SAT and hMSC derived adipocytes showed no dif- et al. ● Pooled SAT preadipocytes from female donors (n = 6), BMI 24.5-28.2 derived adipocytes from donor ferences in expression for AGT mRNA. 2006 [27] (Zen-Bio, Inc.) iliac crest. (USA) Commercial SAT preadipocytes. ADIPOCYTE 7 preadipocyte (pro)renin receptors increased the catalytic SAT [39]. Ye et al. [40] observed that, during adipogen- efficiency of AGT conversion to Ang I. esis of VAT-derived preadipocytes, mRNA expression of AGT and cathepsin (a non-RAS enzyme that can increase Ang II production) increased, whereas renin 3.2.2. Differentiation and RAS components and ACE-1 decreased [40]. In early adipogenesis, AT1R The role of RAS components has been a topic of inter- and AT2R mRNA expression initially increased, and est. Three articles examined AT1R and AT2R expres- then decreased in the later stages. Than et al. showed sion and function using SAT human preadipocytes that AT1R and MasR proteins were expressed in [31–33] (Table 2). Schling et al. noted AT2R mRNA human SAT preadipocytes and adipocytes [41]. Ang and protein expression increased, whereas AT1R (1–7)/MasR promoted adipogenesis by inhibiting the mRNA expression decreased, and protein expression phosphorylation of PPAR-γ, which antagonized the of AT1R remained unchanged, during adipogenesis anti-adipogenic effect of Ang II/AT1R in preadipocytes. [31]. Sysoeva et al. [32] reported human SAT contained In contrast to the other 8 articles describing the anti- a subpopulation of adipose-derived mesenchymal stem adipogenic effect of Ang II, Sarzani et al. [42] found cells that express AT1R and AT2R mRNA and protein, that Ang II stimulated adipogenesis. This is addressed and concluded that adipogenesis required expression of in the Discussion. both AT1R and AT2R, based on an inhibitor strategy Finally, there were 2 articles in which Ang II and [32]. Than et al. reported AT1R and ATR2 proteins 5-azacytidine (5-AZA) were used in an attempt to were present in preadipocytes [33]. Ang II, acting trans-differentiate human adipose-derived MSCs (ad- through ATR2, induced white adipocyte browning by MSCs) into cardiomyocyte-like cells [43,44]. Song increasing PPAR-γ expression. Thyroid hormone T3 et al. [43] obtained a 20% trans-differentiation rate. stimulated the protein expression of AT2R but not Gaafar et al. [44] were unable to induce trans- AT1R to further promote adipocyte browning. differentiation of the ad-MSCs into cardiomyocytes Several articles examined the effect of Ang II on using Ang II and 5-AZA. adipose differentiation [34–42]. Engeli et al. reported a common action of insulin and Ang II to increase nitric oxide (NO) production during differentiation of 3.2.3. RAS and adipose inflammation SAT preadipocytes [34]. Brücher et al. [35] demon- The focus of the investigation was the connection between strated Ang II inhibited the adipogenesis of human RAS and adipose tissue inflammation [45–59] (Table 3). adipocyte progenitor cells from OAT that were induced Several articles have focused on the role of Ang II in this to undergo adipogenesis in vitro [35]. The inhibitory process [45–53]. Goossens et al. administered Ang II locally effect of Ang II was greater in adipocytes from obese into abdominal SAT which led to vasoconstriction and versus non-obese donors and was blocked by ARB reduced blood flow to cause adipose tissue hypoxia [45]. (losartan). Janke et al. demonstrated AGT, or Ang II, This increased mRNA expression of inflammatory markers resulted in a dose-dependent inhibition of adipogenesis such as TNF-α. Harte et al. investigated the effects of TNF- of preadipocytes derived from SAT [36]. The mRNA α, insulin or insulin in combination with rosiglitazone on expression of AGT, renin, ACE-1, and AT1R increased isolated adipocytes from SAT [46]. TNF-α increased AGT during adipogenesis. Inhibition of adipogenesis by Ang and Ang II secretion and insulin increased TNF-, AGT and II was blocked by ARB (irbesartan). Dünner et al. Ang II secretion. Rosiglitazone, a potent PPAR-γ agonist, reported Ang II inhibited differentiation of preadipo- reduced the insulin-mediated rise in TNF-α, AGT and Ang cytes from SAT and OAT into mature adipocytes [37]. II secretion. Menikdiwela et al. found Ang II increased ER Ang II exerted a greater anti-adipogenic effect on pre- stress and increased mRNA levels of NF-κB and its down- adipocytes isolated from individuals with obesity. The stream target IL-6 in adipocytes differentiated from anti-adipogenic effect of Ang II was associated with mesenchymal stem cells [47]. Expression of NF-κB and increased phosphorylation of ERK1/2 (a negative reg- IL-6 mRNA was significantly reduced by ARB (telmisar- ulator of insulin-stimulated Akt phosphorylation) tan). Skurk et al. used SAT adipocytes and noted Ang II which resulted in decreased phosphorylated Akt. enhanced IL-6 and IL-8 protein production and release by Fuentes et al. demonstrated Ang II reduced the adipo- a NF-κB-dependent pathway [48]. The proinflammatory genesis of preadipocytes from OAT [38]. This was response generated by Ang II was reduced by treatment associated with an increase in phosphorylated ERK1/2 with an ARB (candesartan). Polonis et al. demonstrated and an increase in phosphorylation of a key adipogenic intermittent hypoxia-induced inflammation and transcription factor PPAR-γ. Janke et al. [39] found a senescence-like phenotype (SA-β-gal positive cells) in ARBs (irbesartan, losartan, and telmisartan) induced SAT predipocytes. and this was accentuated by the expo- adipogenesis and activated PPAR-γ target genes in sure of preadipocytes to Ang II [49]. It also increased 8 R. TING ET AL. mitochondrial ROS, and treatment with an ARB (losartan) 3.2.4. RAS components associated with blood or ACE inhibitor (captopril) reduced mitochondrial ROS pressure and the percentage of SA-β-gal positive cells. Skurk et al. RAS components have been implicated in the control exposed human SAT adipocytes to Ang II and found of blood pressure [60–66] (Table 4). Factors associated a dose- and time-dependent stimulation of the release of with increased blood pressure and AGT gene expres- PAI-1, which was blocked by ARB (candesartan) [50]. In sion have been reported [60–64]. Serazin et al. treated another study, Skurk et al. [51] treated SAT preadipocytes SAT with cAMP analogue 8Br-cAMP and this with Ang II and observed more leptin secretion in a dose- increased ATG mRNA and protein levels [60]. Prat- and time-dependent manner by an ERK1/2-dependent Larquemin et al. demonstrated that AGT secretion by pathway, and this was inhibited by ARB (candesartan) SAT adipocytes was not related to adipocyte size, BMI, [51]. Li et al. found that AT1R blocker and partial PPAR- blood pressure or M235T AGT gene polymorphism γ agonist (telmisartan) promoted the mRNA expression of [61]. Sarzani et al. analysed AGT promotor variants in adiponectin, an anti-inflammatory adipokine, and human kidney cortex, medulla and perirenal adipose decreased the mRNA levels of the inflammatory markers’ tissue [62]. They found that AGT promotor variants leptin, IL-6 and IL-17, in inflamed mesenteric adipose influenced transcriptional activity in a tissue-specific tissue from patients with Crohn’s disease [52]. Boccara manner and the presence of AGT promotor variants et al. showed that HIV protease inhibitors (PI) increased at −175 and −163 were most highly expressed in the AGT mRNA expression and AT1R protein levels as well as perirenal adipose tissue depot. Park et al. analysed Ang II signalling through an ERK1/2-dependent pathway human AGT promoter polymorphisms for AGT in SAT, and these effects were blocked by ARB (irbesartan mRNA expression and found a significantly higher and telmisartan) [53]. expression of AGT mRNA derived from the −20C allele Adipocyte paracrine interactions with other cell types in comparison to the −20A allele in SAT but not were also studied [54–56]. Blumensatt et al. investigated the omental VAT [63]. Gorzelniak et al. found AGT effect of conditioned medium (CM) produced by human mRNA expression was significantly lower in adipocytes EAT from patients with type 2 diabetes on Lewis rat from obese subjects irrespective of blood pressure [64]. cardiomyocytes [54]. EAT secretory products increased Renin, ACE-1 and AT1R mRNA expression were sig- inflammatory markers and impaired cardiomyocyte func- nificantly higher in patients with obesity and hyperten- tion by reducing sarcomere shortening and increased miR- sion. Hydrocortisone increased AT1R mRNA and 208a expression. The effect was inhibited by the addition of protein expression in a time- and dose-dependent man- ARB (losartan) to EAT-conditioned medium. Rasha et al. ner. Expression of these genes was not affected by treated breast cancer cells with CM from human adipocytes insulin, thyroxine, oestradiol or Ang II. pretreated with ACE inhibitors and eicosapentaenoic acid Malinowski et al. reported that internal thoracic artery (EPA) [55]. The protective effect of ACE inhibitors in rings without, versus with perivascular adipose tissue, lessening adipocyte inflammation in breast cancer cells contracted more strongly in response to Ang II [65]. was increased with EPA. In a second study, Rasha et al. Perivascular adipose tissue decreased Ang II-stimulated demonstrated that Ang II did not directly alter the secre- contraction by releasing nitric oxide (NO) and prostacy- tion of inflammatory cytokines by breast cancer cells [56]. clin-dependent anticontractile factor. Pleural adipose tis- However, treatment of these cells with CM from Ang II- sue did not influence internal thoracic artery reactivity in treated adipocytes did increase their secretion of pro- Ang II. Ehrhart-Bornstein et al. found that treatment of inflammatory proteins. CM from adipocytes treated with adrenocortical cells (NCI-H295R) with conditioned med- an ARB (telmisartan) and ACE inhibitor (captopril) sig- ium (CM) from isolated adipocytes significantly nificantly reduced this effect. increased aldosterone secretion by adrenocortical cells There has been interest in the role of ACE-2 in adipose [66]. This effect is independent of the adipose Ang II. tissue inflammation [57–59]. de Oliveira et al. reported The stimulatory effect of adipocyte CM in the presence of irisin, an anti-inflammatory cytokine, reduced expression an ARB (valsartan) was unaltered. of genes that regulate ACE-2 cleavage in SAT [57]. Patel et al. found ACE-2 protein suppressed EAT inflammation 4. Discussion [58]. Pinheiro et al. [59] noted increased expression of AGT and ACE-1 mRNA, along with that of TNF-α and Our scoping review provides a preliminary assessment IL-6, in VAT of obese and malnourished individuals [59]. of in vitro studies describing the local expression and No significant differences were found for ACE-2 expres- molecular actions of RAS in human adipose cells and sion between groups. tissue. After searching six databases, we retrieved only ADIPOCYTE 9 Table 2. RAS components and differentiation of human adipose tissue-derived cells in vitro studies (N = 14). Study population & Country of Cell type(s) isolated/Source of RAS Component(s) Reference Corresponding Author tissues studied Key Findings Brücher Females (n = 13), Males (n = 11); BMI<30 (n Stroma-vascular preadipocytes Ang II, AT1R, and Ang II reduced recruitment of undifferentiated cells to undergo adipogenic differentiation in vitro. et al. = 15), BMI≥30 (n = 9). from greater omental VAT. AT2R Inhibition of adipogenic differentiation by Ang II correlated directly with BMI. 2007 (Chile) The effect of Ang II was greater on preadipocytes from obese donors. [35] Inhibition of adipogenesis by Ang II was reversed by losartan (AT1R inhibitor). CGP42112A (AT2R inhibitor) did not reverse Ang II inhibition of adipogenesis. Dünner Female donors (n = 14); BMI 34 ± 5.7; Preadipocytes from omental Ang II Ang II signalling in human preadipocytes involved an ERK1/2-dependent attenuation of Akt et al. Simpson-Golabi-Behmel syndrome (SGBS) VAT and activity. 2013 neonates. SGBS neonates. [37] (Chile) Engeli Healthy females 25–60 yrs.; BMI 22–35. Mammary SAT adipocytes and Ang II Insulin and Ang II increased NO production by human preadipocytes in vitro. et al. (Germany) preadipocytes [34] Fuentes Non-obese subjects. Preadipocytes from human Ang II Ang II reduced adipogenesis during the first 48 h of differentiation induction. et al. (Chile) omental fat. Ang II increased phosphorylated PPARϒ and ERK1/2 after induction of adipogenesis. 2010 Inhibition of MEK1 activity prevented ERK1/2 phosphorylation and blocked the anti-adipogenic [38] effect of Ang II. Gaafar Patients undergoing anterior abdominal wall ad-MSCs from abdominal wall Ang II Ang II and 5-azacytidine were unsuccessful in inducing trans-differentiation of human ad-MSCs et al. surgeries. biopsy. into cardiomyocytes in vitro. 2015 (Egypt) [44] Janke et al. Healthy females 20–60 yrs.; BMI 22–35. Preadipocytes and mature AGT, Ang II, AT1R, Adipogenesis was associated with an increase in mRNA expression of AGT, renin, ACE-1, and AT1. 2002 (Germany) adipocytes from mammary AT2R, and ACE-1 Incubation with Ang II or AGT resulted in a dose-dependent inhibition of adipogenesis. [36] SAT. AT1R blockage with irbesartan increased lipid accumulation (increased cells and increased intra- cytoplasmic lipid accumulation). Co-culture of preadipocytes with adipocytes inhibited adipogenesis. Effects were abolished by AT1R blocker. Janke et al. Healthy females 20–60 yrs.; BMI 22–35; Preadipocytes and mature AT1R AT1R blockers (telmisartan, irbesartan and losartan) induced adipogenesis and PPAR-ϒ activation 2006 Healthy males; BMI>30. adipocytes from mammary which increased mRNA and protein expression of lipoprotein lipase and adiponectin in preadi- [39] (Germany) SAT. pocytes. PPAR-ϒ antagonist (GW9662) lowered mRNA and protein expression of lipoprotein lipase and adiponectin. ● ● ● Sarzani Males (n = 8); Perirenal adipocytes and Ang II and AT1R Omental and perirenal preadipocyte proliferation was stimulated by Ang II and inhibited by atrial et al. Post-menopausal females (n = 7) preadipocytes. natriuretic peptide (ANP). ● ● ● 2008 Perirenal avg. age 67.2 yrs (n = 16). Omental adipocytes and Valsartan (ARB) blocked this effect of Ang II. [42] Omental avg. age 69.3 yrs (n = 9). preadipocytes. AT1R, but not AT2R mRNA was expressed in omental adipose tissue. (Italy) Schling Healthy females and males aged 19–63 yrs. Human SAT preadipocytes Ang II, AT1R, and AT1R and AT2R were present in human preadipocytes before, during and after differentiation et al. (Germany) from abdominal or breast AT2R into adipocytes. 2004 surgery. AT1R mRNA declined sharply during adipogenesis; protein levels remain unchanged. [31] AT2R mRNA and protein levels increased during adipogenesis. (Continued ) 10 R. TING ET AL. Table 2. (Continued). Study population & Country of Cell type(s) isolated/Source of RAS Component(s) Reference Corresponding Author tissues studied Key Findings Song et al. Adult female ADSCs from abdominal SAT Ang II Ang II and 5-azacytidine were able to induce trans-differentiation of 20% of the human ad-MSCs 2013 (China) into cardiomyocytes-like cells in vitro. [43] Sysoeva Donors avg. BMI 23.5 ± 2.4 (n = 18) ADSCs from abdominal SAT Ang II, AT1R, AT2R, Human SAT contained a subpopulation of ADSCs constantly co-expressing AT1R and AT2R. et al. (Russia) and ACE-1 Autocrine signalling by Ang II via AT2R increased the ability for ADSCs to undergo adipogenesis. [32] Than et al. Non-diabetic male subjects; BMI 25–29.9 Human SAT preadipocytes. Ang II, AT1R, AT2R, AT1R and MasR protein were co-expressed in human preadipocytes and adipocytes. 2013 (Zen-Bio Inc.) MasR and Ang (1–7) Ang (1-7)/MasR promoted adipogenesis and increased protein expression of PPARϒ. [41] (Singapore) Ang (1–7)/MasR antagonized the anti-adipogenic effect of AngII/AT1R in human preadipocytes. Than et al. Non-diabetic subjects; BMI 25–29.9 Human SAT preadipocytes Ang II, AT1R, and The presence of AT1R and AT2R proteins was confirmed in human white adipocytes. 2017 (Zen-Bio In.) AT2R AT2R activation by Ang II or AT2R agonists (C21) induced white adipocyte browning by increasing [33] (Singapore) PPARϒ protein expression. ● AngII-AT2R enhanced brown adipogenesis. Increased UCP1 protein expression and O consumption was evidence of AT2R induced browning effect. Ye et al. Commercially available cells from ScienCell Human VAT preadipocytes AGT, Ang II, AT1R, Ang II was generated by RAS or non-RAS (cathepsin D). 2009 Research Lab. AT2R, and ACE-1. AGT mRNA increased during adipogenesis. [40] (San Diego, CA). Renin mRNA and ACE-1 mRNA decreased during adipogenesis. (China) Cathepsin D mRNA increased during adipogenesis. AT1R and AT2R mRNA increased in early adipogenesis and then decreased by late adipogenesis. ADIPOCYTE 11 one in vitro human adipose article investigating ACE-2 Several studies examined human adipose RAS in the [33]. Thus, there appeared to be a gap in the existing setting of obesity and changes in BMI. Changes in RAS literature related to this important molecule, especially parameters might correlate with the metabolic state since ACE-2 has been identified as a cellular receptor associated with the lean versus obese phenotype. for the SARS-CoV-2 virus [67]. In addition, obesity was Engeli et al. found that there were higher circulating recognized by the WHO as a risk factor for severe levels of AGT, renin, aldosterone, and ACE-1 in obese COVID-19 outcomes [68]. We postulated more articles versus lean human participants [69]. Weight reduction would be published on human adipose ACE-2, after of 5% body weight in obese subjects lowered these our initial search. Another PubMed search was per- levels. The adipocyte expression of mRNA of renin, formed, from inception to 30 July 2021, to determine ACE-1, and AT1R was higher in adipocytes derived if more articles had been published on human adipose from individuals with obesity [28,59,64]. In the case ACE-2. Our PubMed search identified 14 new articles. of AGT mRNA expression, there was wide inter- All 14 articles were included in our scoping review to individual variability [59,61,64]. reflect a more current assessment of the literature on ACE-2 expression in adipose tissue is altered by human adipose ACE-2. obesity, and obesity is considered a risk factor for In total, there were 50 articles included for this COVID-19 [68,70]. Our search parameters identified scoping review [17–66]. Articles published on human only one article that directly studied the adipose of adipose RAS mainly reported on the expression of its ACE2 expression as a function of COVID-19 infection. components, as well as its impact on differentiation, Favre et al. observed that VAT, but not SAT, expression inflammation, and its relationship to blood pressure of ACE-2 mRNA was associated with severity of regulation. Several publications have indicated that COVID-19 symptoms [23]. During the revision process molecular mechanisms involving human adipose RAS of our review, a very recent article reported actual were associated with conditions such as obesity, inflam- SARS-CoV-2 infection of human adipose tissue; in mation, hypertension, type 2 diabetes, cardiac disease, this study, it appeared that ACE-2 was not the main cancer, and COVID-19. Overall, the body of informa- mediator of viral uptake [10]. tion we evaluated underscored the importance of adi- Other articles, with the advent of the COVID-19 pose RAS in health and disease. pandemic, were motivated to study ACE2 given its previously described role as a viral receptor for SARS- CoV-2. SAT or EAT ACE-2 mRNA expression was higher in individuals with elevated BMI [21,22,24,58]. 4.1. Expression of RAS components Individuals with cardiovascular disease and obesity Our scoping review confirmed that all the components with type 2 diabetes were found to express higher levels of systemic RAS were expressed locally by preadipo- of adipose ACE-2 mRNA in EAT than those without cytes and adipocytes in human adipose tissue at the diabetes [24,26] Weight reduction decreased adipose mRNA and protein level. A variety of adipose tissue ACE-2 mRNA expression [21,22]. RNAseq transcrip- depots were investigated, with SAT being the most tome database analysis found that ACE-2 mRNA levels frequent. Studies comparing VAT and SAT found decreased for individuals post-RYGB surgery. It was a higher expression of RAS components in VAT suggested RYGB surgery could benefit individuals [23,28,30] There were 17 studies which used all female with obesity by reducing the risk for severe SARS- donors and 3 studies which used all male adipose tissue CoV-2 infections [21]. donors (Tables 1–4). Studies which compared male and In a cross-sectional analysis, Pinheiro et al. [59] female ACE-2 mRNA expression found no differences found only a slight increase in ACE-2 expression at [17,19,22,24]. In comparison to preadipocytes, adipo- higher BMI that was not significant. cytes expressed higher mRNA levels of AGT, renin, Another area of interest early on in the COVID-19 AT1R and ACE-2 as well as higher protein levels of pandemic was the risk of COVID-19 for individuals Ang II, Ang (1–7) and MasR [29,31,33,40]. On the using ARBs [71]. Studies in rats had indicated that the other hand, preadipocytes expressed higher levels of use of ARBs had the potential to upregulate ACE-2 ACE-1 and (pro)renin receptors in comparison to adi- mRNA expression [72,73]. Articles in our review pocytes [28–30,40]. Studies have shown that the stage approached this issue by examining ACE-2 expression of differentiation influenced the extent of expression in the context of ARB treatment. One study indicated differently depending on the component of interest. that patients with cardiovascular disease and diabetes This might reflect different functions of these molecules who were treated with ARBs had higher ACE-2 mRNA in the progenitor versus the mature cell. expression in EAT but not in SAT [24]. Another study 12 R. TING ET AL. Table 3. RAS components and inflammation in vitro studies (N = 15). RAS Study population & Country of Corresponding Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings Blumensatt Epicardial adipose tissue (EAT) biopsies from Human EAT; Lewis rats’ cardiomyocytes Ang II and Cardiomyocytes exposed to EAT adipocyte conditioned medium (CM) from et al. 2017 patients with and without type 2 diabetes AT1R, ACE-2 patients with type 2 diabetes reduced sarcomere shortening and increased miR- [54] undergoing heart surgery. 208a expression. (Germany) CM from EAT adipocytes pretreated with Losartan from patients with type 2 diabetes no longer had this effect. No difference in ACE-2 between patients. Boccara et al. Healthy participants; BMI<25. (Zen-Bio, Research Preadipocytes from human SAT. AGT, Ang II, HIV protease inhibitors (PI) increased expression of AT1R protein, AGT mRNA and 2010 [53] Triangle Park, NC, USA). and AT1R amplified the effect of Ang II on ERK1/2 activity. (France) ARBs (irbesartan, telmisartan) inhibited PI effects. Rosiglitazone normalized AT1R protein expression. GW9662 (PPAR-γ antagonist) increased AT1R protein expression and increased PI toxicity. Pinheiro Eutrophic patients, obese patients, and Visceral white adipose tissue (VAT) AGT, ACE-1, AGT and ACE mRNA levels were significantly higher in VAT from either obese or et al. 2017 malnourished patients. and ACE-2 malnourished vs. eutrophic groups. [59] (Brazil) No significant difference in ACE-2 mRNA expression between the groups. IL-6 and TNF-α mRNA expressions were significantly higher in VAT from obese or malnourishe vs. eutrophic groups. de Oliveira Commercially available cells from Sigma-Aldrich Human SAT preadipocytes. ACE-2 Irisin regulated the expression of TLR3 genes that play a role in the regulation of et al. 2020 (St. Louis, MO, USA). ACE-2 cleavage. [57] (Brazil) Goossens Male: Lean<25 (n = 9), normal glucose tolerance; Abdominal SAT biopsy Ang II Local administration of Ang II to abdominal SAT decreased adipose tissue blood et al. 2011 Obese>30 (n = 10) impaired glucose tolerance. flow and PO and increased mRNA expression of inflammatory markers such as [45] (Netherlands) TNF-α. Harte et al. White, nondiabetic female subjects; Adipocytes from abdominal SAT AGT and Ang Human SAT was a significant source of Ang II. 2005 [46] Age 42.3 ± 16 yrs.; BMI 29.8 ± 5.4. II Insulin increased TNF-α secretion which in turn increased the Ang II. (United Kingdom) Rosiglitazone downregulated RAS in SAT. Li, Yi et al. Patients with active Crohn’s disease (n = 6): Mesenteric adipose tissue (MAT) AT1R MAT treated with telmisartan significantly increased mRNA expression of adiponectin 2015 [52] activity index>150 and CRP>10. specimen from intestinal wall adjacent to and leptin and decreased mRNA expression of IL-6 and IL-17. (China) disease involved intestine. Menikdiwela Commercially available cells purchased from LONZA Human mesenchymal stem cells (HMSC) AGT, AT1R, Ang II treatment increased inflammation and endoplasmic reticulum (ER) stress in et al. 2019 (Allendale, NJ, USA). AT2R, ACE-1 adipocytes mainly via AT1R. [47] (USA) Telmisartan reduced ER stress and inflammation. Captopril did not reduce ER stress markers. Patel et al. Non-obese subjects, non-failing hearts vs. Obese Epicardial adipose tissue (EAT) ACE-2 HFPEF subjects with obesity had increased ACE-2 protein levels in EAT. 2016 [58] subjects (BMI>30) with HFPEF, hypertension or HFPEF subjects with obesity had increased inflammatory markers in EAT. transplant vasculopathy. (USA) (Continued ) ADIPOCYTE 13 Table 3. (Continued). RAS Study population & Country of Corresponding Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings Polonis et al. ● OSA and non-OSA subjects (n = 50) ● Abdominal SAT from subjects. AT1R, ACE-1 ● Exposure of preadipocytes to Ang II increased mitochondrial ROS production, DNA 2020 [49] ● Commercially available primary human white ● Primary human white abdominal damage, and a higher percentage of SA-β-gal positive cells (senescence) in preadipocytes from abdominal tissue of healthy preadipocytes. preadipocytes. individuals (ZenBio Inc. NC). Treatment of preadipocytes with ARB (losartan) or ACE-1 inhibitor (captopril) (USA) inhibited the effects of Ang II. ● ● ● Rasha et al. Human breast cancer cells from ATCC MDA-MB-231 TNBC and ER/PR posi- ACE-1 Treatment of breast cancer (BC) cells with conditioned medium (CM) from adipo- 2020a [55] (Manassas, VA, USA). tive MCF-7. cytes pretreated with captopril significantly reduced expression of proinflamma- ● ● Bone-marrow-HMSC from Lonza (Allendale, NJ, HMSC tory cytokines and decreased BC cell migration compared to the control group. USA). Treatment of BC cells with CM from adipocytes pretreated with captopril and (USA) Eicosapentaenoic acid (EPA) further enhanced the positive effects of captopril. Rasha et al. ● Human breast cancer cells from ATCC ● MDA-MB-231 TNBC and ER/PR posi- Ang II, AT1R ● Treatment of BC cell lines with conditioned medium (CM) from adipocytes pre- 2020b [56] (Manassas, VA, USA). tive MCF-7. and ACE-1 treated with Ang II significantly increased inflammatory tumour promoters in BC ● Bone-marrow-HMSC from Lonza (Allendale, NJ, ● HMSC cells. USA). Treatment of BC cell lines with conditioned medium from adipocytes pretreated (USA) with telmisartan or captopril significantly reduced markers of inflammation, fatty acid synthesis and angiogenesis in BC cell lines. Skurk et al. Females 18–45 yrs.; Mammary SAT Preadipocytes Ang II and Exposure of human adipocytes to Ang II resulted in a dose- and time-dependent 2001 [50] BMI<26. AT1R stimulation of PAI-1 release. (Germany) Candesartan inhibited action of Ang II indicating effect was mediated by AT1R. Skurk et al. Females 18–50 yrs.; Mammary SAT Pre-adipocytes Ang II, AT1R ● Ang II significantly increased IL-6 and IL-8 production and release by a NF- 2004 [48] BMI≤26. and AT2R B-dependent pathway. (Germany) Pro-inflammatory action of Ang II was primarily mediated by AT1R versus AT2R. Skurk et al. Healthy young or middle-aged women; Stromal cells isolated from mammary SAT Ang II and Ang II increased leptin secretion into the culture medium in a dose- and time- 2005 [51] BMI 20–27 AT1R dependent fashion. (Germany) 14 R. TING ET AL. investigating SAT from patients with or without dia- adipogenic potential of ADSCs corresponded to AT2R betes showed treatment with an ARB (valsartan had no expression [32]. Gene expression of AT1R and AT2R correlation with ACE-2 mRNA expression in SAT) was dependent on the stage of adipogenesis increasing [26]. More studies on adipose depot-dependent mod- initially and then decreasing in the later stages [40]. ifications and molecular mechanisms related to regula- The Ang (1–7)/MasR pathway has also been found to tion of ACE-2 mRNA levels by ARBs are needed. be involved in the autocrine regulation of adipogenesis. Although higher levels of ACE-2 may provide more The inhibitory effects of Ang II/ATR1 could be offset cellular receptors for SARS-CoV-2, higher levels of by Ang (1–7)/MasR [41]. Our scoping study showed ACE-2 may also be theoretically protective by counter- a gap in knowledge for the mechanistic role of human balancing the negative effects of ang II. adipose AT2R and Ang(1–7)/MasR in adipogenesis. Adipose tissue depots are heterogeneous. SAT has been shown to contain white adipocytes as well as 4.2. Differentiation and RAS components clusters of beige adipocytes [75]. Beige adipocytes share the same thermogenic capacity as brown adipo- Adipogenesis is an important process for maintaining cytes, which is important for heat production and proper adipose tissue function in healthy individuals energy expenditure. Individuals with obesity have [6,74]. Local adipose RAS has been shown to play been found to have lower amounts of beige adipocytes a critical role in the regulation of adipogenesis [32]. [76,77]. Beige adipocytes are emerging as novel thera- Obesity-related complications such as type 2 diabetes peutic targets for the treatment of obesity-related dis- have been associated with adipocyte dysfunction due to eases [33]. Than et al. [33] enhanced brown adipocyte hypertrophy. The inability of adipose tissue adipogenesis by promoting AT2R signalling through to expand through adipocyte hyperplasia can cause inhibition of AT1R inhibition. Thyroid hormone T3 adipocyte hypertrophy. This can in turn lead to adipose promoted brown adipogenesis by selectively stimulat- dysfunction and loss of insulin sensitivity [6,74]. The ing AT2R without altering the expression of AT1R, majority of the studies we identified concluded that ACE-1, ACE-2 or AGT [33]. Further research is Ang II inhibited adipogenesis [31–41]. The anti- required to investigate the formation of beige adipo- adipogenic effect of Ang II was mediated through its cytes and the role of AT2R in this process. interaction with AT1R. In vitro studies have indicated ADSCs are a promising stem cell type for cell-based that the adipogenesis is stimulated through the PPAR-γ therapies. ADSCs are an abundant and accessible source pathway and inhibited through the ERK1/2 pathway of adult stem cells with the ability to differentiate along [38]. Stimulation of the ERK1/2 pathway by Ang II multiple lineage pathways [78]. Animal studies have has also been shown to inhibit insulin stimulated Akt indicated that the injection of ADSCs improves cardiac phosphorylation [37]. Ang II/AT1R decreased the function through differentiation into cardiomyocytes and activity of PPAR-γ and increased the activity of vascular cells through paracrine pathways [79,80]. In our ERK1/2 [38]. The addition of ARBs blocked the anti- scoping review, we found two studies, which used pre- adipogenic effects of Ang II by activation of PPAR-γ cursor stem cells for in vitro trans-differentiation of car- [39]. The anti-adipogenic effects of Ang II appeared to diomyocytes with limited success [43,44]. There will be significantly greater in VAT-derived adipocytes likely be further advancements in this area in the future. from individuals with higher BMIs [35,37]. Adipocyte progenitor cells isolated from individuals with higher BMIs displayed less of an adipogenic response [35,37]. 4.3. RAS and adipose inflammation Furthermore, several studies indicated that the anti- adipogenic effects of Ang II were associated with insu- With prolonged positive energy balance, hypertrophied lin resistance [36–39,41]. The only article that reported adipocytes reach a threshold that causes cellular stress Ang II promoted adipogenesis was by Sarzani et al. and initiates an inflammatory programme. Inflamed [42]. They suggest differences in AT1R versus AT2R, adipocytes secrete pro-inflammatory cytokines, which as well as concentrations of reagents, may account for can disrupt the normal function of adipose tissue as their findings. well as that of remote organs [81]. In vitro studies The expression of AGT gene expression increased showed that adipocyte pro-inflammatory cytokines during adipogenesis. The presence of AT1R and AT2R had the ability to influence the growth and migration was also required for adipogenesis [32,40]. Both pre- of breast cancer cells [55,56]. Chronic low-grade adipocytes and adipocytes were found to express AT1R inflammation in adipose tissue has been shown to be proteins [31,32,41]. Mature adipocytes expressed AT2R, a risk factor for the development of insulin resistance however, not all ADSCs expressed AT2R [32]. The and type 2 diabetes in individuals with obesity [82]. ADIPOCYTE 15 Table 4. RAS components and blood pressure in vitro studies (N = 7). Study population & Country of Corresponding RAS Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings ● ● Ehrhart- Healthy females 20–35 yrs. (n = 10); Mammary SAT adipocytes. Ang II and AT1R Stimulation of aldosterone secretion by NCI-H295R cells was not mediated Bornstein BMI 21.4–29.2 Adrenal NCI-H295R cells by Ang II. et al. 2003 (Germany) [66] ● ● Gorzelniak Hypertensive females BP > 130/80 (n = 30): Adipocytes from: AGT, Ang II, AT1R, Detected AGT, renin, ACE-1, AT1R and AT2R mRNA expression in adipo- et al. 2002 Obese (BMI > 30); Lean (BMI < 25); abdominal SAT needle biopsy of periumbilical AT2R, renin and cytes but AT2R was barely detectable. [64] biopsy. region. ACE-1 ● Insulin, thyroxine, oestradiol, and Ang II had no significant effect on the Healthy females (n = 4) 34–60 yrs.; BMI 23–31; Mammary SAT. expression of RAS genes studied. breast reduction. Hydrocortisone increased AT1R mRNA expression. (Germany) AGT mRNA expression was significantly lower in obese vs. non-obese. ● Renin, ACE-1 and AT1R mRNA expression was significantly higher in obesity vs. non-obese. Hypertensive obese subjects had the highest AT1R mRNA. Malinowski Patients undergoing surgery for stable isolated Perivascular adipose tissue (PVT) of Ang II PVT significantly decreased the ITA contractility response to serotonin and et al. 2008 coronary artery disease. internal thoracic artery (ITA); Pleural Ang II. [65] (USA) adipose tissue PVT of ITA released nitric oxide (NO) and prostacyclin-independent antic- ontractile factor. Pleural adipose tissue presence did not change the ITA contractility response to serotonin and Ang II. Park et al. 2013 Males (n = 21); SAT and omental VAT. AGT Significantly higher AGT mRNA expression for −20C allele versus −20A [63] Females (n = 24). allele in SAT. (USA) No significant difference in −20C and −20A allele AGT mRNA expression was detected in omental VAT. Prat-Larquemin Females 22–61 yrs. (n = 61); BMI≥28. Mature adipocytes from peri-umbilical SAT AGT Higher levels of AGT secretion in human adipocytes, with greater inter- et al. 2004 (France) needle aspiration individual variation, in comparison to rat adipocytes. [61] AGT secretion was not related to adipocyte size, BMI, blood pressure or M235T AGT gene polymorphism. Adipocyte size differed among AGT genotypes. Sarzani et al. Consecutive patients undergoing radical Visceral adipose tissue (VAT). AGT AGT promotor variants −175 and −163 expressed higher levels of AGT mRNA 2010 [62] nephrectomy (n = 35). in perirenal VAT than tissue from kidney cortex or kidney medulla. Mean: 64.6-yr-old; BMI 27.3 (Italy) Serazin et al. Males (57 ± 8.5 yrs.); BMI 26.2 ± 3.2 (n = 4). SAT fragments AGT Increased adipocyte AGT expression and secretion by cAMP suggested the 2004 [60] (France) sympathetic nervous system may have a role in the activation of the local RAS. cAMP increased the expression and secretion of human AGT in SAT. 16 R. TING ET AL. Many molecular mechanisms operating within adipo- [46] One study found that AGT secretion by SAT cytes have been suggested as possible regulators of human adipocytes was not associated with increased inflammation, including ER stress, hypoxia and cellular blood pressure [61]. Additionally, Ang II reduced thor- senescence. acic ring contraction through the release of NO in Adipose RAS has been shown to play a role in perivascular adipose tissue [34,65]. Another study adipose tissue inflammation. Local administration of found that hypertension was associated with lower Ang II induced tissue hypoxia and increased the levels of AGT and higher levels of renin, ACE-1 and expression of inflammatory markers [45]. Both insulin AT1R mRNA expression in SAT [64]; the inconsistent and TNF-α increased the secretion of AGT and Ang II findings among these studies have been attributed to secretion by adipocytes [46]. In preadipocytes, exposure differences in study population to Ang II increased mitochondrial ROS and increased markers associated with senescence [49]. In adipocytes, 4.5. Strengths and limitations of the study Ang II exposure was shown to increase ER stress and increase levels of NF-κB and its downstream target IL-6 The review applied a systematic and rigorous search [47]. Ang II could also stimulate the release of pro- strategy to retrieve relevant articles according to the thrombotic plasminogen activator inhibitor-1 (PAI-1) research objectives. We used a scoping review to iden- [50]. The undesirable effects of Ang II were inhibited tify the nature and breadth of the current evidence by treatment with ARBs, which indicated that the pro- available. An assessment of the quality of the included inflammatory pathways were associated with Ang II studies is not the usual expectation of scoping reviews interaction with AT1R [47–51]. Additionally, one and thus was not included, which is a potential limita- study found that treatment with ARB reduced inflam- tion of our study. However, we selected only peer- matory markers secreted by mesenteric adipose tissue reviewed primary literature as part of our screening from patients with Crohn’s disease [52]. criteria. Our study summarizes scientific findings and Conversely, ACE-2 has been associated with an anti- highlights significant heterogeneity in several areas inflammatory role. Patients with higher levels of ACE-2 including adipose tissue source and variations in the in epicardial tissue had a lower risk of inflammation- methodology used to characterize adipose RAS. It iden- related issues [58]. Another study associated the reduc- tifies literature gaps and suggests some directions for tion in ACE-2 cleavage in SAT with the anti- future research initiatives on human adipose RAS. inflammatory effects of irisin [57]. Furthermore, ACE- A major limitation of our study was that our data- 2 enzyme can convert Ang II to Ang(1–7) [41]. The base search was conducted on 24 June 2020. Our study Ang(1–7)/MasR pathway has been associated with the showed the state of research available at an early stage counter-regulation of AngII/AT1R [41]. Thus, an of the pandemic. Thus, it would be informative in increase in conversion of Ang II to Ang (1–7) could a future study to compare our study with the state of have the potential to reduce inflammation. research currently available as the pandemic has pro- gressed. Our study was also limited to articles published in the English language. Owing to the broad scope of 4.4. RAS components associated with blood study methodologies used to analyse adipose tissue, the pressure database search strategy was limited by including only Systemic RAS is important for blood pressure control. studies with the term ‘in vitro’ in the MESH heading Various components of human adipose RAS have been used in the search strategy. Furthermore, the COVID- studied for their possible role in systemic blood pres- 19 pandemic has generated a new interest in adipose sure regulation. AGT is a precursor of Ang II, the ACE-2, and there has been an escalation in publica- principal effector hormone for blood pressure regula- tions. Although this scoping review does not capture all tion. A number of studies have investigated the role of articles due to this recent rapid acceleration, it does adipose AGT for blood pressure regulation in humans. serve as a landmark of current information, and has Sympathetic stimulation of adipocytes from SAT with the potential to become a reference point for future a cAMP analogue was shown to increase AGT gene investigations in this area. expression [60]. However, there were many variables associated with AGT gene expression, which included 5. Conclusions a wide inter-individual as well as tissue-specific varia- bility [59,61,62,64,64]. Harte et al. found Ang II that This scoping review was conducted as a preliminary was produced locally in abdominal SAT and was assessment of the state of the literature published a significant source of Ang II in the systemic circulation related to in vitro human adipose RAS from 2001 to ADIPOCYTE 17 2021. 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In vitro studies of the renin-angiotensin system in human adipose tissue/adipocytes and possible relationship to SARS-CoV-2: a scoping review

Adipocyte , Volume 12 (1): 1 – Dec 31, 2023

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ADIPOCYTE 2023, VOL. 12, NO. 1, 2194034 https://doi.org/10.1080/21623945.2023.2194034 REVIEW In vitro studies of the renin-angiotensin system in human adipose tissue/ adipocytes and possible relationship to SARS-CoV-2: a scoping review a a,b,c a,b,c,d Ryan Ting , Heidi Dutton , and Alexander Sorisky a b c Faculty of Medicine, University of Ottawa, Ottawa, Canada; Department of Medicine, University of Ottawa, Ottawa, Canada; The Ottawa Hospital/Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada ABSTRACT ARTICLE HISTORY The renin-angiotensin system (RAS) operates within adipose tissue. Obesity-related changes can Received 27 September 2022 affect adipose RAS, predisposing to hypertension, type 2 diabetes, and possibly severe COVID-19. Revised 20 December 2022 Accepted 2 January 2023 We evaluated the in vitro research on human adipose RAS and identified gaps in the literature. Medline (Ovid), Embase (Ovid), Web of Science, Scopus, and 1findr were searched to identify KEYWORDS relevant studies. Fifty primary studies met our inclusion criteria for analysis. Expression of RAS Renin-angiotensin system; components (n = 14), role in differentiation (n = 14), association with inflammation (n = 15) or adipose tissue; human; blood pressure (n = 7) were investigated. We found (1) obesity-related changes in RAS were in vitro studies frequently studied (30%); (2) an upswing of articles investigating adipose ACE-2 expression since the COVID-19 pandemic; (3) a paucity of papers on AT2R and Ang (1–7)/MasR which counterbalance Ang II/ART1; (4) weight loss lowered adipose ACE-2 mRNA expression; and (5) angiotensin receptor blockers (ARBs) reduced deleterious effects of angiotensin II. Overall, these studies link Ang II/ATR1 signalling to impaired adipogenesis and a pro-inflammatory dysfunctional adipose tissue, with ATR1 blockade limiting these responses. ACE-2 may mitigate Ang II effects by converting it to Ang(1–7) which binds MasR. More work is needed to understand adipose RAS in various pathologic states such as obesity and COVID-19 infection.T. 1. Introduction The renin-angiotensin system (RAS) is involved in the peptides that act locally or enter the circulation to regulation of blood pressure, electrolyte balance, exert distant effects. Adipocytes produce and secrete inflammation, and tissue remodelling. [1] all of the described RAS components [4]. Angiotensinogen (AGT) is released from the liver and Adipose tissue is a multi-depot organ and plays is cleaved to form angiotensin I (Ang I) by renin a role in energy regulation and inflammation/immu- secreted from the kidneys. Ang I is then processed by nity. RAS in adipose tissue plays an important role in angiotensin converting enzyme-1 (ACE-1) to form adipogenesis as well as in lipid/glucose metabolism and angiotensin II (Ang II). Other non-RAS enzymes such inflammation [5]. Obesity-associated pro-inflammatory as cathepsin D can also cleave AGT to produce Ang II and oxidative stress results from adipocyte hypertrophy [2]. Ang II interacts with angiotensin type 1 receptors and associated cellular hypoxia [6]. This increases (AT1R) and angiotensin type 2 receptors (AT2R) to macrophage infiltration into adipose tissue promoting exert its physiological effects. This includes vasocon- expression of inflammatory mediators and dysregula- striction of vascular smooth muscle cells and aldoster- tion of adipokines such Ang II. An increase in Ang II one release from the adrenal cortex, leading to sodium has been suggested to contribute to obesity-associated and water retention and an increase in blood pressure hypertension and insulin resistance [5]. [2]. Ang II is cleaved by angiotensin converting Adipose RAS may potentially contribute to the enzyme-2 (ACE-2) to Ang (1–7) which interacts with body’s response to viral infections. In 2003, a global Mas receptors (MasR) to counteract the vasoconstric- outbreak of severe respiratory syndrome caused by tor-promoting effects of Ang II [3]. Several tissues coronavirus SARS-CoV-1 resulted in 916 deaths [7]. possess their own RAS and generate angiotensin From 24 January 2020 to 30 July 2021, the global CONTACT Alexander Sorisky asorisky@ohri.ca Chronic Disease Program, OHRI, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada Supplemental data for this article can be accessed online at https://doi.org/10.1080/21623945.2023.2194034 © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 R. TING ET AL. pandemic of COVID-19 caused by coronavirus SARS- 24 June 2020: MEDLINE, EMBASE, PubMed, Web of CoV-2 has resulted in 4,248,387 deaths [8]. The SARS- Science, Scopus, and 1findr. The search strategies were CoV-1 and SARS-CoV-2 viruses selectively bind to drafted in consultation with an information specialist ACE-2 to infect human cells and may reduce ACE-2 (KF) and further refined through team discussion with locally or systemically [9]. Recently, SARS-CoV-2 RNA all authors. A pretested combination of keywords and has been detected in adipocytes [10]. The reduction of MESH terms were used based upon the identified core ACE-2 could disrupt Ang II/AT1R and Ang (1–7)/ concepts of the research question: (1) adipose tissue/ MasR homoeostasis [11]. Increased Ang II levels have cells; (2) renin-angiotensin system; (3) in vitro. been associated with vasoconstriction, inflammation, A detailed search strategy for MEDLINE (Ovid) is cell proliferation, hypertrophy, fibrosis, and tissue shown in Supporting Information S1. Additional remodelling [12]. Individuals with obesity are at high sources of information included reference lists from risk for severe COVID-19 infections, and it has been retrieved papers [16]. suggested higher levels of ACE-2 in adipose cells may We also searched PubMed on 30 July 2021 using the lead to this tissue acting as a reservoir for viral spread terms ‘human’, ‘adipose’, and ‘ACE-2’ to identify the within an individual [9]. Therefore, reviewing what is ongoing activity of ACE-2 publications after the first known about the human cellular function of adipose search was completed. RAS is timely and pertinent. We undertook a scoping review to provide 2.4. Study selection a preliminary assessment of this broad and complex emerging topic. The primary objective was to provide Eligibility criteria were established based on research an overview of in vitro research investigating the func- questions and pretested in PubMed. Primary research tion of RAS in adipose tissue/adipocytes derived from articles written in English that fulfiled the following human cell lines or human adipose tissue, and its criteria were included in the analysis: (i) a component possible association with SARS-CoV-2. Our secondary of the renin-angiotensin system was investigated; (ii) at objective is to identify uncertainties or gaps in the least one indicator of cellular expression of RAS in existing literature, providing a framework for future adipose tissue/adipocytes was identified; (iii) studies research initiatives. were performed with human adipose/adipocytes or human cell lines in vitro; (4) studies were related to adipose tissue or adipocyte function. We did not 2. Methods include animal cell studies in this defined scoping review, as they are not as relevant and immediate as 2.1. Methodological approach human cell studies are to the understanding of clinical The review process was based on the methodological disease states. framework proposed by Arksey and O’Malley [13]. The Studies excluded from this study were as follows: (i) review was conducted in accordance with the Preferred manual duplicates (ii) review articles and meta-analysis; Reporting Items for Systematic reviews and Meta- (iii) studies for which the full-text article did not exist Analyses extension for Scoping Reviews (PRISMA- such as a conference/abstract; (iv) editorials/commen- ScR) checklist guidelines [14,15]. Registration for scop- taries; (v) in vivo human studies that did not include ing reviews on PROSPERO (the NIH international isolated adipose tissue/adipocytes or human adipose prospective register of systematic reviews) was not cell lines; (vi) studies performed with other human available at the time this article was prepared. cells that did not include adipose tissue/adipocytes; (vii) in vitro studies which did not examine the effect of RAS in human adipose tissue/adipocytes; (viii) 2.2. Research question and key concepts in vitro studies involving adipose tissue/adipocytes What are the extent and nature of in vitro research from animal-derived tissue (transgenic animals), cells, investigating the renin-angiotensin system in human and cell lines; (ix) studies reported in languages for adipose tissue/adipocytes? What is the possible associa- which no English language translation was available. tion of human adipose RAS with SARS-CoV-2? 2.5. Screening 2.3. Database search All the retrieved records from the databases and hand- To identify relevant documents, the following biblio- searches were imported in Zotero reference manage- graphic databases were searched from inception to ment database (version 5.0 Corporation for Digital ADIPOCYTE 3 Scholarship, Roy Rosenzweig Center for History and 3.2. Study characteristics New Media, George Mason University, Fairfax, VA, The publication period of the 50 eligible studies ranged USA). The records were then converted into a RIS from 2001 to 2021. Of these, 14 studies investigated format for import into Covidence systematic review expression of RAS components, 14 studies investigated software, Veritas Health Innovation, Melbourne, RAS and differentiation, 15 studies investigated RAS Australia (available at www.covidence.org) which was and inflammation, and 7 studies investigated RAS and used for screening. In order to minimize bias, titles and blood pressure. Tables 1–4 contain specific details of abstracts of studies identified by the systematic search each study such as those related to age, gender, depot of were screened for relevance by two independent inves- adipose tissue and country. tigators, AS and RT. Relevant articles identified through the screen were reviewed for complete assess- 3.2.1. Expression of RAS components ment of eligibility criteria. Discrepancies were resolved Assessing ACE-2 expression in adipose tissue has through discussion and consensus. A third reviewer, grown in interest recently, given its possible role as HD, was available to resolve any conflicts. a SAR-CoV-2 viral receptor with respect to obesity and susceptibility to COVID-19 infection. A variety of adipose depots were examined. Four articles detected 2.6. Data extraction high ACE-2 gene expression in adipose tissue relative to other tissue types [17–20] (Table 1). The other four Prior to the search, a data extraction form was designed to articles examined ACE-2 mRNA expression in relation facilitate interpretation, comparison, and synthesis of the to BMI [21–24]. Kristem et al. used GEO datasets to findings from the included studies. Pretesting of the data measure ACE-2 gene expression in subcutaneous white extraction form was performed by RT on five papers, adipose tissue (SAT) from patients with severe obesity, which then led to further refinement of the form after before and after Roux-en-Y gastric bypass (RYGB); discussion with the other authors. RT conducted the results showed RYGB was associated with lower ACE- extraction. AS verified the data extraction to ensure accu- 2 mRNA expression [21]. Similarly, Li, L et al. observed racy and reproducibility. The final version of the form that weight loss was associated with a decline in SAT included: authors, publication year, paper title, journal, ACE-2 mRNA [22]. Favre et al. noted that expression country of senior/corresponding author, purpose, study of ACE-2 mRNA paralleled BMI in visceral adipose population, cell type(s) isolated/source of tissues, compo- tissue (VAT) from overweight patients, and has been nents of RAS studied, methodology (study design), the only publication to correlate that in patients with or experimental treatments, key findings, and sponsorship. without COVID-19 infection [23]. Couselo-Seijas et al. found ACE-2 and ADAM17 (its cleavage enzyme) mRNA expression levels were higher in epicardial adi- 3. Results pose tissue (EAT) from patients with type 2 diabetes mellitus and ACE-2 was highest in patients with obesity 3.1. Study selection and diabetes [24]. Desterke et al. found ACE-2 mRNA Our initial search strategy conducted on 24 June 2020 was highly expressed in adipose-derived mesenchymal identified 3232 articles. Removal of duplicates by stem cells (MSC) [25]. deLigt et al. studies participants Covidence resulted in 1390 unique articles. After who received either valsartan or placebo for 26 weeks screening titles and abstracts for relevance, 62 studies [26]. Abdominal SAT biopsies were collected before were eligible for full-text review. Of these articles, 26 and after 26 weeks of treatment. There were no signifi- were excluded for the following reasons: not conducted cant differences in ACE-2, AGT, ACE-1 and AT1R in human adipose tissue/cells (n = 11), full text not mRNA expression in SAT between the valsartan or available (n = 9), manual duplicates (n = 5), no discus- placebo groups. sion section (n = 1). This left 36 studies to review. Four of the 14 articles examined the expression of RAS A PubMed search was conducted on 30 July 2021 to components other than ACE-2 [27–30]. Mackay et al. capture articles for ACE-2 published after our initial demonstrated that AGT mRNA expression was similar in database search. Additional 14 studies were retrieved. medullary adipocytes, human mesenchymal stem cell- Therefore, 50 studies were included in this scoping derived adipocytes and subcutaneous adipocytes [27]. review [17–66] (Figure 1). Fain et al. observed that most of the in vitro release of 4 R. TING ET AL. Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram. ACE-1 from adipose tissue was by stromal non-fat cells AT1R mRNA was greater in adipocytes than preadipo- and more ACE-1 was released by omental adipose tissue cytes, whereas renin receptor mRNA expression was (OAT) from patients with class III obesity > 40 kg/m equal between adipocytes and preadipocytes, and the (mean BMI 46 kg/m ) versus patients with class I obesity expression of ACE-1 mRNA was lower in adipocytes 2 2 BMI 30–35 kg/m (mean BMI 32.9 kg/m ) [28]. Fain than preadipocytes. Archard et al. reported (pro)renin et al. compared mRNA expression from adipocytes ver- receptors were synthesized in the stromal portion of sus preadipocytes for AGT, renin receptor, AT1R and human adipose tissue (SAT and OAT) in preadipocytes ACE-1 in OAT [29]. The expression of AGT mRNA and and non-preadipocyte cells [30]. Renin binding to ADIPOCYTE 5 Table 1. Expression of RAS components in human adipose tissue in vitro studies (N = 14). RAS Component(s) Reference Study population & Country of Corresponding Author Cell type(s) isolated/Source of tissues studied Key Findings Archard Females 18–55 yrs.: Stromal preadipocytes from biopsies AGT, and RenR was localized in the cell periphery. et al. BMI 21.0 ± 2.2 (n = 14); BMI 37.9 ± 5.2 (n = 17) of abdominal SAT and omental VAT. Renin receptor Renin binding to RenR of preadipocyte cells in vitro stimulated 2007 [30] (France) (RenR) intracellular-signalling pathways and potentiated AGT to Ang I generation. RenR expression was higher in VAT. Couselo- 36 patients who underwent open-heart surgery. Age 70 ± 0.8 yrs. Females Epicardial fat (EAT) and SAT biopsies; ACE-1, and Similar levels of ACE-1 in EAT and SAT. Seijas (n = 11); Male (n = 25); Obese and non-obese BMI 30 ± 0.95; diabetic and Stromal vascular cells (n = 8). ACE-2 EAT expressed higher levels of ACE-2 and lower ADAM17 mRNA et al. non-diabetic patients. than SAT. 2021 [24] (Spain) EAT and SAT from cardiac patients with obesity and T2DM had the highest levels of ACE-2 mRNA. Diabetic patients treated with ARBs had higher ACE-2 mRNA levels than diabetic patients not treated with ARBs. de Ligt et al. Impaired glucose metabolism. Abdominal SAT biopsy. AGT, AT1R, Expression of AGT, ACE-1, ACE-2 and AT1R mRNA in group 2021 [26] BMI 31 ± 0.8 (n = 36) ACE-1, and treated for 26 weeks with valsartan was not significantly dif- (Netherlands) ACE-2 ferent from the placebo group. Desterke Transcriptome datasets from Gene Expression Omnibus (GEO) website. Human mesenchymal stem cells ACE-2 ACE-2 mRNA was highly expressed in adult bone marrow, et al. (France) (hMSC). adipose tissue, and umbilical cord-derived hMSC. 2021 [25] Fain et al. Female avg. 39 yrs. Explants of abdominal SAT, and ACE-1 The majority of the in vitro release of ACE-1 was from non-fat 2007 [28] Obese: omental VAT. (Non-fat cell and cells. Mean BMI 32.9 (n = 10) adipocyte fractions) Higher levels of ACE-1 are released by adipose tissue from Morbidly obese: subjects with morbid obesity. Mean BMI 46 (n = 12). Higher levels of ACE-1 released by omental VAT versus SAT (USA) explants. Fain et al. Female avg. 40 yrs. Stromovascular portion of omental AGT, AT1R, Adipocyte versus non-adipocyte mRNA: AGT is higher in adi- 2008 [29] Morbidly obese avg. VAT. ACE-1 and pocytes and RenR lower in adipocytes. BMI 46 RenR Adipocyte vs. preadipocyte mRNA: AGT & AT1R higher in adipo- (USA) cytes; RenR same; ACE-1 lower in adipocytes. Favre et al. Non-obese patients with and without COVID-19. VAT and SAT ACE-2 Positive correlation between ACE2 mRNA and BMI in VAT, but 2021 [23] (France) not SAT. Higher ACE2 with COVID-19 ACE-2 was not related to age and sex. Han et al. RNAseq transcriptome and sex data from the genotype-tissue expression Human tissues ACE-2 ACE-2 mRNA levels were highest in the small intestines. 2020 [17] (GTEx) and the Cancer Genome Atlas (TCGA). ACE-2 mRNA levels were high in salivary glands, testicular, kid- (China) ney, heart, thyroid and adipose tissue. No significant sexual differences in ACE2 gene expression. Kerslake Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), and Human tissue ACE-2 ACE-2 mRNA was expressed in adipose tissue. et al. GEPIA (http://gepia.cancer). 2020 [18] (United Kingdom) (Continued ) 6 R. TING ET AL. Table 1. (Continued). RAS Component(s) Reference Study population & Country of Corresponding Author Cell type(s) isolated/Source of tissues studied Key Findings Kristem Gene Expression Omnibus (GEO) Data Sets. SAT pre- and post- Roux-en-Y gastric ACE-2 ● After RYGB, mRNA expression of ACE-2 in SAT decreased. et al. Females avg. 47 years: Obese (n = 16); non-obese (n = 16) bypass (RYGB) ACE-2 in SAT was lower in post-RYGB patients vs non-obese 2021 [21] (USA) matched controls. Li, L et al. Age>18 yrs. SAT biopsy ACE-2 No difference in ACE-2 mRNA expression for males and females 2020 [22] Obese (n = 156); and differences in age. Female (n = 120); ACE-2 mRNA expression was reduced in insulin-resistant subjects. Male (n = 36) ACE-2 mRNA expression was correlated with adipose leptin pro- (Germany) duction. ACE-2 mRNA expression was lower after BMI reduction and improved insulin sensitivity. Li, M et al. GTEx datasets (RSEM normalized) from UCSC Xena project, TCGA datasets Human tissues ACE-2 ACE-2 mRNA expression levels in adipose tissue were high in 2020 [19] from Genomic Data Commons Data Portal. comparison to other tissue types. (China) No difference in ACE2 mRNA expression between males and females or between younger and older persons in any tissues. Liu, et al. GTEx database; COVID-19 host genetics initiative 2020. Human tissues ACE-2 ACE-2 mRNA was found in adipose tissue. 2021 [20] (Sweden) ● ● ● Mackay Donors aged 22–27 yrs. hMSC and medullary adipocytes. Medullary adipocytes and hMSC AGT Medullary, SAT and hMSC derived adipocytes showed no dif- et al. ● Pooled SAT preadipocytes from female donors (n = 6), BMI 24.5-28.2 derived adipocytes from donor ferences in expression for AGT mRNA. 2006 [27] (Zen-Bio, Inc.) iliac crest. (USA) Commercial SAT preadipocytes. ADIPOCYTE 7 preadipocyte (pro)renin receptors increased the catalytic SAT [39]. Ye et al. [40] observed that, during adipogen- efficiency of AGT conversion to Ang I. esis of VAT-derived preadipocytes, mRNA expression of AGT and cathepsin (a non-RAS enzyme that can increase Ang II production) increased, whereas renin 3.2.2. Differentiation and RAS components and ACE-1 decreased [40]. In early adipogenesis, AT1R The role of RAS components has been a topic of inter- and AT2R mRNA expression initially increased, and est. Three articles examined AT1R and AT2R expres- then decreased in the later stages. Than et al. showed sion and function using SAT human preadipocytes that AT1R and MasR proteins were expressed in [31–33] (Table 2). Schling et al. noted AT2R mRNA human SAT preadipocytes and adipocytes [41]. Ang and protein expression increased, whereas AT1R (1–7)/MasR promoted adipogenesis by inhibiting the mRNA expression decreased, and protein expression phosphorylation of PPAR-γ, which antagonized the of AT1R remained unchanged, during adipogenesis anti-adipogenic effect of Ang II/AT1R in preadipocytes. [31]. Sysoeva et al. [32] reported human SAT contained In contrast to the other 8 articles describing the anti- a subpopulation of adipose-derived mesenchymal stem adipogenic effect of Ang II, Sarzani et al. [42] found cells that express AT1R and AT2R mRNA and protein, that Ang II stimulated adipogenesis. This is addressed and concluded that adipogenesis required expression of in the Discussion. both AT1R and AT2R, based on an inhibitor strategy Finally, there were 2 articles in which Ang II and [32]. Than et al. reported AT1R and ATR2 proteins 5-azacytidine (5-AZA) were used in an attempt to were present in preadipocytes [33]. Ang II, acting trans-differentiate human adipose-derived MSCs (ad- through ATR2, induced white adipocyte browning by MSCs) into cardiomyocyte-like cells [43,44]. Song increasing PPAR-γ expression. Thyroid hormone T3 et al. [43] obtained a 20% trans-differentiation rate. stimulated the protein expression of AT2R but not Gaafar et al. [44] were unable to induce trans- AT1R to further promote adipocyte browning. differentiation of the ad-MSCs into cardiomyocytes Several articles examined the effect of Ang II on using Ang II and 5-AZA. adipose differentiation [34–42]. Engeli et al. reported a common action of insulin and Ang II to increase nitric oxide (NO) production during differentiation of 3.2.3. RAS and adipose inflammation SAT preadipocytes [34]. Brücher et al. [35] demon- The focus of the investigation was the connection between strated Ang II inhibited the adipogenesis of human RAS and adipose tissue inflammation [45–59] (Table 3). adipocyte progenitor cells from OAT that were induced Several articles have focused on the role of Ang II in this to undergo adipogenesis in vitro [35]. The inhibitory process [45–53]. Goossens et al. administered Ang II locally effect of Ang II was greater in adipocytes from obese into abdominal SAT which led to vasoconstriction and versus non-obese donors and was blocked by ARB reduced blood flow to cause adipose tissue hypoxia [45]. (losartan). Janke et al. demonstrated AGT, or Ang II, This increased mRNA expression of inflammatory markers resulted in a dose-dependent inhibition of adipogenesis such as TNF-α. Harte et al. investigated the effects of TNF- of preadipocytes derived from SAT [36]. The mRNA α, insulin or insulin in combination with rosiglitazone on expression of AGT, renin, ACE-1, and AT1R increased isolated adipocytes from SAT [46]. TNF-α increased AGT during adipogenesis. Inhibition of adipogenesis by Ang and Ang II secretion and insulin increased TNF-, AGT and II was blocked by ARB (irbesartan). Dünner et al. Ang II secretion. Rosiglitazone, a potent PPAR-γ agonist, reported Ang II inhibited differentiation of preadipo- reduced the insulin-mediated rise in TNF-α, AGT and Ang cytes from SAT and OAT into mature adipocytes [37]. II secretion. Menikdiwela et al. found Ang II increased ER Ang II exerted a greater anti-adipogenic effect on pre- stress and increased mRNA levels of NF-κB and its down- adipocytes isolated from individuals with obesity. The stream target IL-6 in adipocytes differentiated from anti-adipogenic effect of Ang II was associated with mesenchymal stem cells [47]. Expression of NF-κB and increased phosphorylation of ERK1/2 (a negative reg- IL-6 mRNA was significantly reduced by ARB (telmisar- ulator of insulin-stimulated Akt phosphorylation) tan). Skurk et al. used SAT adipocytes and noted Ang II which resulted in decreased phosphorylated Akt. enhanced IL-6 and IL-8 protein production and release by Fuentes et al. demonstrated Ang II reduced the adipo- a NF-κB-dependent pathway [48]. The proinflammatory genesis of preadipocytes from OAT [38]. This was response generated by Ang II was reduced by treatment associated with an increase in phosphorylated ERK1/2 with an ARB (candesartan). Polonis et al. demonstrated and an increase in phosphorylation of a key adipogenic intermittent hypoxia-induced inflammation and transcription factor PPAR-γ. Janke et al. [39] found a senescence-like phenotype (SA-β-gal positive cells) in ARBs (irbesartan, losartan, and telmisartan) induced SAT predipocytes. and this was accentuated by the expo- adipogenesis and activated PPAR-γ target genes in sure of preadipocytes to Ang II [49]. It also increased 8 R. TING ET AL. mitochondrial ROS, and treatment with an ARB (losartan) 3.2.4. RAS components associated with blood or ACE inhibitor (captopril) reduced mitochondrial ROS pressure and the percentage of SA-β-gal positive cells. Skurk et al. RAS components have been implicated in the control exposed human SAT adipocytes to Ang II and found of blood pressure [60–66] (Table 4). Factors associated a dose- and time-dependent stimulation of the release of with increased blood pressure and AGT gene expres- PAI-1, which was blocked by ARB (candesartan) [50]. In sion have been reported [60–64]. Serazin et al. treated another study, Skurk et al. [51] treated SAT preadipocytes SAT with cAMP analogue 8Br-cAMP and this with Ang II and observed more leptin secretion in a dose- increased ATG mRNA and protein levels [60]. Prat- and time-dependent manner by an ERK1/2-dependent Larquemin et al. demonstrated that AGT secretion by pathway, and this was inhibited by ARB (candesartan) SAT adipocytes was not related to adipocyte size, BMI, [51]. Li et al. found that AT1R blocker and partial PPAR- blood pressure or M235T AGT gene polymorphism γ agonist (telmisartan) promoted the mRNA expression of [61]. Sarzani et al. analysed AGT promotor variants in adiponectin, an anti-inflammatory adipokine, and human kidney cortex, medulla and perirenal adipose decreased the mRNA levels of the inflammatory markers’ tissue [62]. They found that AGT promotor variants leptin, IL-6 and IL-17, in inflamed mesenteric adipose influenced transcriptional activity in a tissue-specific tissue from patients with Crohn’s disease [52]. Boccara manner and the presence of AGT promotor variants et al. showed that HIV protease inhibitors (PI) increased at −175 and −163 were most highly expressed in the AGT mRNA expression and AT1R protein levels as well as perirenal adipose tissue depot. Park et al. analysed Ang II signalling through an ERK1/2-dependent pathway human AGT promoter polymorphisms for AGT in SAT, and these effects were blocked by ARB (irbesartan mRNA expression and found a significantly higher and telmisartan) [53]. expression of AGT mRNA derived from the −20C allele Adipocyte paracrine interactions with other cell types in comparison to the −20A allele in SAT but not were also studied [54–56]. Blumensatt et al. investigated the omental VAT [63]. Gorzelniak et al. found AGT effect of conditioned medium (CM) produced by human mRNA expression was significantly lower in adipocytes EAT from patients with type 2 diabetes on Lewis rat from obese subjects irrespective of blood pressure [64]. cardiomyocytes [54]. EAT secretory products increased Renin, ACE-1 and AT1R mRNA expression were sig- inflammatory markers and impaired cardiomyocyte func- nificantly higher in patients with obesity and hyperten- tion by reducing sarcomere shortening and increased miR- sion. Hydrocortisone increased AT1R mRNA and 208a expression. The effect was inhibited by the addition of protein expression in a time- and dose-dependent man- ARB (losartan) to EAT-conditioned medium. Rasha et al. ner. Expression of these genes was not affected by treated breast cancer cells with CM from human adipocytes insulin, thyroxine, oestradiol or Ang II. pretreated with ACE inhibitors and eicosapentaenoic acid Malinowski et al. reported that internal thoracic artery (EPA) [55]. The protective effect of ACE inhibitors in rings without, versus with perivascular adipose tissue, lessening adipocyte inflammation in breast cancer cells contracted more strongly in response to Ang II [65]. was increased with EPA. In a second study, Rasha et al. Perivascular adipose tissue decreased Ang II-stimulated demonstrated that Ang II did not directly alter the secre- contraction by releasing nitric oxide (NO) and prostacy- tion of inflammatory cytokines by breast cancer cells [56]. clin-dependent anticontractile factor. Pleural adipose tis- However, treatment of these cells with CM from Ang II- sue did not influence internal thoracic artery reactivity in treated adipocytes did increase their secretion of pro- Ang II. Ehrhart-Bornstein et al. found that treatment of inflammatory proteins. CM from adipocytes treated with adrenocortical cells (NCI-H295R) with conditioned med- an ARB (telmisartan) and ACE inhibitor (captopril) sig- ium (CM) from isolated adipocytes significantly nificantly reduced this effect. increased aldosterone secretion by adrenocortical cells There has been interest in the role of ACE-2 in adipose [66]. This effect is independent of the adipose Ang II. tissue inflammation [57–59]. de Oliveira et al. reported The stimulatory effect of adipocyte CM in the presence of irisin, an anti-inflammatory cytokine, reduced expression an ARB (valsartan) was unaltered. of genes that regulate ACE-2 cleavage in SAT [57]. Patel et al. found ACE-2 protein suppressed EAT inflammation 4. Discussion [58]. Pinheiro et al. [59] noted increased expression of AGT and ACE-1 mRNA, along with that of TNF-α and Our scoping review provides a preliminary assessment IL-6, in VAT of obese and malnourished individuals [59]. of in vitro studies describing the local expression and No significant differences were found for ACE-2 expres- molecular actions of RAS in human adipose cells and sion between groups. tissue. After searching six databases, we retrieved only ADIPOCYTE 9 Table 2. RAS components and differentiation of human adipose tissue-derived cells in vitro studies (N = 14). Study population & Country of Cell type(s) isolated/Source of RAS Component(s) Reference Corresponding Author tissues studied Key Findings Brücher Females (n = 13), Males (n = 11); BMI<30 (n Stroma-vascular preadipocytes Ang II, AT1R, and Ang II reduced recruitment of undifferentiated cells to undergo adipogenic differentiation in vitro. et al. = 15), BMI≥30 (n = 9). from greater omental VAT. AT2R Inhibition of adipogenic differentiation by Ang II correlated directly with BMI. 2007 (Chile) The effect of Ang II was greater on preadipocytes from obese donors. [35] Inhibition of adipogenesis by Ang II was reversed by losartan (AT1R inhibitor). CGP42112A (AT2R inhibitor) did not reverse Ang II inhibition of adipogenesis. Dünner Female donors (n = 14); BMI 34 ± 5.7; Preadipocytes from omental Ang II Ang II signalling in human preadipocytes involved an ERK1/2-dependent attenuation of Akt et al. Simpson-Golabi-Behmel syndrome (SGBS) VAT and activity. 2013 neonates. SGBS neonates. [37] (Chile) Engeli Healthy females 25–60 yrs.; BMI 22–35. Mammary SAT adipocytes and Ang II Insulin and Ang II increased NO production by human preadipocytes in vitro. et al. (Germany) preadipocytes [34] Fuentes Non-obese subjects. Preadipocytes from human Ang II Ang II reduced adipogenesis during the first 48 h of differentiation induction. et al. (Chile) omental fat. Ang II increased phosphorylated PPARϒ and ERK1/2 after induction of adipogenesis. 2010 Inhibition of MEK1 activity prevented ERK1/2 phosphorylation and blocked the anti-adipogenic [38] effect of Ang II. Gaafar Patients undergoing anterior abdominal wall ad-MSCs from abdominal wall Ang II Ang II and 5-azacytidine were unsuccessful in inducing trans-differentiation of human ad-MSCs et al. surgeries. biopsy. into cardiomyocytes in vitro. 2015 (Egypt) [44] Janke et al. Healthy females 20–60 yrs.; BMI 22–35. Preadipocytes and mature AGT, Ang II, AT1R, Adipogenesis was associated with an increase in mRNA expression of AGT, renin, ACE-1, and AT1. 2002 (Germany) adipocytes from mammary AT2R, and ACE-1 Incubation with Ang II or AGT resulted in a dose-dependent inhibition of adipogenesis. [36] SAT. AT1R blockage with irbesartan increased lipid accumulation (increased cells and increased intra- cytoplasmic lipid accumulation). Co-culture of preadipocytes with adipocytes inhibited adipogenesis. Effects were abolished by AT1R blocker. Janke et al. Healthy females 20–60 yrs.; BMI 22–35; Preadipocytes and mature AT1R AT1R blockers (telmisartan, irbesartan and losartan) induced adipogenesis and PPAR-ϒ activation 2006 Healthy males; BMI>30. adipocytes from mammary which increased mRNA and protein expression of lipoprotein lipase and adiponectin in preadi- [39] (Germany) SAT. pocytes. PPAR-ϒ antagonist (GW9662) lowered mRNA and protein expression of lipoprotein lipase and adiponectin. ● ● ● Sarzani Males (n = 8); Perirenal adipocytes and Ang II and AT1R Omental and perirenal preadipocyte proliferation was stimulated by Ang II and inhibited by atrial et al. Post-menopausal females (n = 7) preadipocytes. natriuretic peptide (ANP). ● ● ● 2008 Perirenal avg. age 67.2 yrs (n = 16). Omental adipocytes and Valsartan (ARB) blocked this effect of Ang II. [42] Omental avg. age 69.3 yrs (n = 9). preadipocytes. AT1R, but not AT2R mRNA was expressed in omental adipose tissue. (Italy) Schling Healthy females and males aged 19–63 yrs. Human SAT preadipocytes Ang II, AT1R, and AT1R and AT2R were present in human preadipocytes before, during and after differentiation et al. (Germany) from abdominal or breast AT2R into adipocytes. 2004 surgery. AT1R mRNA declined sharply during adipogenesis; protein levels remain unchanged. [31] AT2R mRNA and protein levels increased during adipogenesis. (Continued ) 10 R. TING ET AL. Table 2. (Continued). Study population & Country of Cell type(s) isolated/Source of RAS Component(s) Reference Corresponding Author tissues studied Key Findings Song et al. Adult female ADSCs from abdominal SAT Ang II Ang II and 5-azacytidine were able to induce trans-differentiation of 20% of the human ad-MSCs 2013 (China) into cardiomyocytes-like cells in vitro. [43] Sysoeva Donors avg. BMI 23.5 ± 2.4 (n = 18) ADSCs from abdominal SAT Ang II, AT1R, AT2R, Human SAT contained a subpopulation of ADSCs constantly co-expressing AT1R and AT2R. et al. (Russia) and ACE-1 Autocrine signalling by Ang II via AT2R increased the ability for ADSCs to undergo adipogenesis. [32] Than et al. Non-diabetic male subjects; BMI 25–29.9 Human SAT preadipocytes. Ang II, AT1R, AT2R, AT1R and MasR protein were co-expressed in human preadipocytes and adipocytes. 2013 (Zen-Bio Inc.) MasR and Ang (1–7) Ang (1-7)/MasR promoted adipogenesis and increased protein expression of PPARϒ. [41] (Singapore) Ang (1–7)/MasR antagonized the anti-adipogenic effect of AngII/AT1R in human preadipocytes. Than et al. Non-diabetic subjects; BMI 25–29.9 Human SAT preadipocytes Ang II, AT1R, and The presence of AT1R and AT2R proteins was confirmed in human white adipocytes. 2017 (Zen-Bio In.) AT2R AT2R activation by Ang II or AT2R agonists (C21) induced white adipocyte browning by increasing [33] (Singapore) PPARϒ protein expression. ● AngII-AT2R enhanced brown adipogenesis. Increased UCP1 protein expression and O consumption was evidence of AT2R induced browning effect. Ye et al. Commercially available cells from ScienCell Human VAT preadipocytes AGT, Ang II, AT1R, Ang II was generated by RAS or non-RAS (cathepsin D). 2009 Research Lab. AT2R, and ACE-1. AGT mRNA increased during adipogenesis. [40] (San Diego, CA). Renin mRNA and ACE-1 mRNA decreased during adipogenesis. (China) Cathepsin D mRNA increased during adipogenesis. AT1R and AT2R mRNA increased in early adipogenesis and then decreased by late adipogenesis. ADIPOCYTE 11 one in vitro human adipose article investigating ACE-2 Several studies examined human adipose RAS in the [33]. Thus, there appeared to be a gap in the existing setting of obesity and changes in BMI. Changes in RAS literature related to this important molecule, especially parameters might correlate with the metabolic state since ACE-2 has been identified as a cellular receptor associated with the lean versus obese phenotype. for the SARS-CoV-2 virus [67]. In addition, obesity was Engeli et al. found that there were higher circulating recognized by the WHO as a risk factor for severe levels of AGT, renin, aldosterone, and ACE-1 in obese COVID-19 outcomes [68]. We postulated more articles versus lean human participants [69]. Weight reduction would be published on human adipose ACE-2, after of 5% body weight in obese subjects lowered these our initial search. Another PubMed search was per- levels. The adipocyte expression of mRNA of renin, formed, from inception to 30 July 2021, to determine ACE-1, and AT1R was higher in adipocytes derived if more articles had been published on human adipose from individuals with obesity [28,59,64]. In the case ACE-2. Our PubMed search identified 14 new articles. of AGT mRNA expression, there was wide inter- All 14 articles were included in our scoping review to individual variability [59,61,64]. reflect a more current assessment of the literature on ACE-2 expression in adipose tissue is altered by human adipose ACE-2. obesity, and obesity is considered a risk factor for In total, there were 50 articles included for this COVID-19 [68,70]. Our search parameters identified scoping review [17–66]. Articles published on human only one article that directly studied the adipose of adipose RAS mainly reported on the expression of its ACE2 expression as a function of COVID-19 infection. components, as well as its impact on differentiation, Favre et al. observed that VAT, but not SAT, expression inflammation, and its relationship to blood pressure of ACE-2 mRNA was associated with severity of regulation. Several publications have indicated that COVID-19 symptoms [23]. During the revision process molecular mechanisms involving human adipose RAS of our review, a very recent article reported actual were associated with conditions such as obesity, inflam- SARS-CoV-2 infection of human adipose tissue; in mation, hypertension, type 2 diabetes, cardiac disease, this study, it appeared that ACE-2 was not the main cancer, and COVID-19. Overall, the body of informa- mediator of viral uptake [10]. tion we evaluated underscored the importance of adi- Other articles, with the advent of the COVID-19 pose RAS in health and disease. pandemic, were motivated to study ACE2 given its previously described role as a viral receptor for SARS- CoV-2. SAT or EAT ACE-2 mRNA expression was higher in individuals with elevated BMI [21,22,24,58]. 4.1. Expression of RAS components Individuals with cardiovascular disease and obesity Our scoping review confirmed that all the components with type 2 diabetes were found to express higher levels of systemic RAS were expressed locally by preadipo- of adipose ACE-2 mRNA in EAT than those without cytes and adipocytes in human adipose tissue at the diabetes [24,26] Weight reduction decreased adipose mRNA and protein level. A variety of adipose tissue ACE-2 mRNA expression [21,22]. RNAseq transcrip- depots were investigated, with SAT being the most tome database analysis found that ACE-2 mRNA levels frequent. Studies comparing VAT and SAT found decreased for individuals post-RYGB surgery. It was a higher expression of RAS components in VAT suggested RYGB surgery could benefit individuals [23,28,30] There were 17 studies which used all female with obesity by reducing the risk for severe SARS- donors and 3 studies which used all male adipose tissue CoV-2 infections [21]. donors (Tables 1–4). Studies which compared male and In a cross-sectional analysis, Pinheiro et al. [59] female ACE-2 mRNA expression found no differences found only a slight increase in ACE-2 expression at [17,19,22,24]. In comparison to preadipocytes, adipo- higher BMI that was not significant. cytes expressed higher mRNA levels of AGT, renin, Another area of interest early on in the COVID-19 AT1R and ACE-2 as well as higher protein levels of pandemic was the risk of COVID-19 for individuals Ang II, Ang (1–7) and MasR [29,31,33,40]. On the using ARBs [71]. Studies in rats had indicated that the other hand, preadipocytes expressed higher levels of use of ARBs had the potential to upregulate ACE-2 ACE-1 and (pro)renin receptors in comparison to adi- mRNA expression [72,73]. Articles in our review pocytes [28–30,40]. Studies have shown that the stage approached this issue by examining ACE-2 expression of differentiation influenced the extent of expression in the context of ARB treatment. One study indicated differently depending on the component of interest. that patients with cardiovascular disease and diabetes This might reflect different functions of these molecules who were treated with ARBs had higher ACE-2 mRNA in the progenitor versus the mature cell. expression in EAT but not in SAT [24]. Another study 12 R. TING ET AL. Table 3. RAS components and inflammation in vitro studies (N = 15). RAS Study population & Country of Corresponding Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings Blumensatt Epicardial adipose tissue (EAT) biopsies from Human EAT; Lewis rats’ cardiomyocytes Ang II and Cardiomyocytes exposed to EAT adipocyte conditioned medium (CM) from et al. 2017 patients with and without type 2 diabetes AT1R, ACE-2 patients with type 2 diabetes reduced sarcomere shortening and increased miR- [54] undergoing heart surgery. 208a expression. (Germany) CM from EAT adipocytes pretreated with Losartan from patients with type 2 diabetes no longer had this effect. No difference in ACE-2 between patients. Boccara et al. Healthy participants; BMI<25. (Zen-Bio, Research Preadipocytes from human SAT. AGT, Ang II, HIV protease inhibitors (PI) increased expression of AT1R protein, AGT mRNA and 2010 [53] Triangle Park, NC, USA). and AT1R amplified the effect of Ang II on ERK1/2 activity. (France) ARBs (irbesartan, telmisartan) inhibited PI effects. Rosiglitazone normalized AT1R protein expression. GW9662 (PPAR-γ antagonist) increased AT1R protein expression and increased PI toxicity. Pinheiro Eutrophic patients, obese patients, and Visceral white adipose tissue (VAT) AGT, ACE-1, AGT and ACE mRNA levels were significantly higher in VAT from either obese or et al. 2017 malnourished patients. and ACE-2 malnourished vs. eutrophic groups. [59] (Brazil) No significant difference in ACE-2 mRNA expression between the groups. IL-6 and TNF-α mRNA expressions were significantly higher in VAT from obese or malnourishe vs. eutrophic groups. de Oliveira Commercially available cells from Sigma-Aldrich Human SAT preadipocytes. ACE-2 Irisin regulated the expression of TLR3 genes that play a role in the regulation of et al. 2020 (St. Louis, MO, USA). ACE-2 cleavage. [57] (Brazil) Goossens Male: Lean<25 (n = 9), normal glucose tolerance; Abdominal SAT biopsy Ang II Local administration of Ang II to abdominal SAT decreased adipose tissue blood et al. 2011 Obese>30 (n = 10) impaired glucose tolerance. flow and PO and increased mRNA expression of inflammatory markers such as [45] (Netherlands) TNF-α. Harte et al. White, nondiabetic female subjects; Adipocytes from abdominal SAT AGT and Ang Human SAT was a significant source of Ang II. 2005 [46] Age 42.3 ± 16 yrs.; BMI 29.8 ± 5.4. II Insulin increased TNF-α secretion which in turn increased the Ang II. (United Kingdom) Rosiglitazone downregulated RAS in SAT. Li, Yi et al. Patients with active Crohn’s disease (n = 6): Mesenteric adipose tissue (MAT) AT1R MAT treated with telmisartan significantly increased mRNA expression of adiponectin 2015 [52] activity index>150 and CRP>10. specimen from intestinal wall adjacent to and leptin and decreased mRNA expression of IL-6 and IL-17. (China) disease involved intestine. Menikdiwela Commercially available cells purchased from LONZA Human mesenchymal stem cells (HMSC) AGT, AT1R, Ang II treatment increased inflammation and endoplasmic reticulum (ER) stress in et al. 2019 (Allendale, NJ, USA). AT2R, ACE-1 adipocytes mainly via AT1R. [47] (USA) Telmisartan reduced ER stress and inflammation. Captopril did not reduce ER stress markers. Patel et al. Non-obese subjects, non-failing hearts vs. Obese Epicardial adipose tissue (EAT) ACE-2 HFPEF subjects with obesity had increased ACE-2 protein levels in EAT. 2016 [58] subjects (BMI>30) with HFPEF, hypertension or HFPEF subjects with obesity had increased inflammatory markers in EAT. transplant vasculopathy. (USA) (Continued ) ADIPOCYTE 13 Table 3. (Continued). RAS Study population & Country of Corresponding Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings Polonis et al. ● OSA and non-OSA subjects (n = 50) ● Abdominal SAT from subjects. AT1R, ACE-1 ● Exposure of preadipocytes to Ang II increased mitochondrial ROS production, DNA 2020 [49] ● Commercially available primary human white ● Primary human white abdominal damage, and a higher percentage of SA-β-gal positive cells (senescence) in preadipocytes from abdominal tissue of healthy preadipocytes. preadipocytes. individuals (ZenBio Inc. NC). Treatment of preadipocytes with ARB (losartan) or ACE-1 inhibitor (captopril) (USA) inhibited the effects of Ang II. ● ● ● Rasha et al. Human breast cancer cells from ATCC MDA-MB-231 TNBC and ER/PR posi- ACE-1 Treatment of breast cancer (BC) cells with conditioned medium (CM) from adipo- 2020a [55] (Manassas, VA, USA). tive MCF-7. cytes pretreated with captopril significantly reduced expression of proinflamma- ● ● Bone-marrow-HMSC from Lonza (Allendale, NJ, HMSC tory cytokines and decreased BC cell migration compared to the control group. USA). Treatment of BC cells with CM from adipocytes pretreated with captopril and (USA) Eicosapentaenoic acid (EPA) further enhanced the positive effects of captopril. Rasha et al. ● Human breast cancer cells from ATCC ● MDA-MB-231 TNBC and ER/PR posi- Ang II, AT1R ● Treatment of BC cell lines with conditioned medium (CM) from adipocytes pre- 2020b [56] (Manassas, VA, USA). tive MCF-7. and ACE-1 treated with Ang II significantly increased inflammatory tumour promoters in BC ● Bone-marrow-HMSC from Lonza (Allendale, NJ, ● HMSC cells. USA). Treatment of BC cell lines with conditioned medium from adipocytes pretreated (USA) with telmisartan or captopril significantly reduced markers of inflammation, fatty acid synthesis and angiogenesis in BC cell lines. Skurk et al. Females 18–45 yrs.; Mammary SAT Preadipocytes Ang II and Exposure of human adipocytes to Ang II resulted in a dose- and time-dependent 2001 [50] BMI<26. AT1R stimulation of PAI-1 release. (Germany) Candesartan inhibited action of Ang II indicating effect was mediated by AT1R. Skurk et al. Females 18–50 yrs.; Mammary SAT Pre-adipocytes Ang II, AT1R ● Ang II significantly increased IL-6 and IL-8 production and release by a NF- 2004 [48] BMI≤26. and AT2R B-dependent pathway. (Germany) Pro-inflammatory action of Ang II was primarily mediated by AT1R versus AT2R. Skurk et al. Healthy young or middle-aged women; Stromal cells isolated from mammary SAT Ang II and Ang II increased leptin secretion into the culture medium in a dose- and time- 2005 [51] BMI 20–27 AT1R dependent fashion. (Germany) 14 R. TING ET AL. investigating SAT from patients with or without dia- adipogenic potential of ADSCs corresponded to AT2R betes showed treatment with an ARB (valsartan had no expression [32]. Gene expression of AT1R and AT2R correlation with ACE-2 mRNA expression in SAT) was dependent on the stage of adipogenesis increasing [26]. More studies on adipose depot-dependent mod- initially and then decreasing in the later stages [40]. ifications and molecular mechanisms related to regula- The Ang (1–7)/MasR pathway has also been found to tion of ACE-2 mRNA levels by ARBs are needed. be involved in the autocrine regulation of adipogenesis. Although higher levels of ACE-2 may provide more The inhibitory effects of Ang II/ATR1 could be offset cellular receptors for SARS-CoV-2, higher levels of by Ang (1–7)/MasR [41]. Our scoping study showed ACE-2 may also be theoretically protective by counter- a gap in knowledge for the mechanistic role of human balancing the negative effects of ang II. adipose AT2R and Ang(1–7)/MasR in adipogenesis. Adipose tissue depots are heterogeneous. SAT has been shown to contain white adipocytes as well as 4.2. Differentiation and RAS components clusters of beige adipocytes [75]. Beige adipocytes share the same thermogenic capacity as brown adipo- Adipogenesis is an important process for maintaining cytes, which is important for heat production and proper adipose tissue function in healthy individuals energy expenditure. Individuals with obesity have [6,74]. Local adipose RAS has been shown to play been found to have lower amounts of beige adipocytes a critical role in the regulation of adipogenesis [32]. [76,77]. Beige adipocytes are emerging as novel thera- Obesity-related complications such as type 2 diabetes peutic targets for the treatment of obesity-related dis- have been associated with adipocyte dysfunction due to eases [33]. Than et al. [33] enhanced brown adipocyte hypertrophy. The inability of adipose tissue adipogenesis by promoting AT2R signalling through to expand through adipocyte hyperplasia can cause inhibition of AT1R inhibition. Thyroid hormone T3 adipocyte hypertrophy. This can in turn lead to adipose promoted brown adipogenesis by selectively stimulat- dysfunction and loss of insulin sensitivity [6,74]. The ing AT2R without altering the expression of AT1R, majority of the studies we identified concluded that ACE-1, ACE-2 or AGT [33]. Further research is Ang II inhibited adipogenesis [31–41]. The anti- required to investigate the formation of beige adipo- adipogenic effect of Ang II was mediated through its cytes and the role of AT2R in this process. interaction with AT1R. In vitro studies have indicated ADSCs are a promising stem cell type for cell-based that the adipogenesis is stimulated through the PPAR-γ therapies. ADSCs are an abundant and accessible source pathway and inhibited through the ERK1/2 pathway of adult stem cells with the ability to differentiate along [38]. Stimulation of the ERK1/2 pathway by Ang II multiple lineage pathways [78]. Animal studies have has also been shown to inhibit insulin stimulated Akt indicated that the injection of ADSCs improves cardiac phosphorylation [37]. Ang II/AT1R decreased the function through differentiation into cardiomyocytes and activity of PPAR-γ and increased the activity of vascular cells through paracrine pathways [79,80]. In our ERK1/2 [38]. The addition of ARBs blocked the anti- scoping review, we found two studies, which used pre- adipogenic effects of Ang II by activation of PPAR-γ cursor stem cells for in vitro trans-differentiation of car- [39]. The anti-adipogenic effects of Ang II appeared to diomyocytes with limited success [43,44]. There will be significantly greater in VAT-derived adipocytes likely be further advancements in this area in the future. from individuals with higher BMIs [35,37]. Adipocyte progenitor cells isolated from individuals with higher BMIs displayed less of an adipogenic response [35,37]. 4.3. RAS and adipose inflammation Furthermore, several studies indicated that the anti- adipogenic effects of Ang II were associated with insu- With prolonged positive energy balance, hypertrophied lin resistance [36–39,41]. The only article that reported adipocytes reach a threshold that causes cellular stress Ang II promoted adipogenesis was by Sarzani et al. and initiates an inflammatory programme. Inflamed [42]. They suggest differences in AT1R versus AT2R, adipocytes secrete pro-inflammatory cytokines, which as well as concentrations of reagents, may account for can disrupt the normal function of adipose tissue as their findings. well as that of remote organs [81]. In vitro studies The expression of AGT gene expression increased showed that adipocyte pro-inflammatory cytokines during adipogenesis. The presence of AT1R and AT2R had the ability to influence the growth and migration was also required for adipogenesis [32,40]. Both pre- of breast cancer cells [55,56]. Chronic low-grade adipocytes and adipocytes were found to express AT1R inflammation in adipose tissue has been shown to be proteins [31,32,41]. Mature adipocytes expressed AT2R, a risk factor for the development of insulin resistance however, not all ADSCs expressed AT2R [32]. The and type 2 diabetes in individuals with obesity [82]. ADIPOCYTE 15 Table 4. RAS components and blood pressure in vitro studies (N = 7). Study population & Country of Corresponding RAS Component(s) Reference Author Cell type(s) isolated/Source of tissues studied Key Findings ● ● Ehrhart- Healthy females 20–35 yrs. (n = 10); Mammary SAT adipocytes. Ang II and AT1R Stimulation of aldosterone secretion by NCI-H295R cells was not mediated Bornstein BMI 21.4–29.2 Adrenal NCI-H295R cells by Ang II. et al. 2003 (Germany) [66] ● ● Gorzelniak Hypertensive females BP > 130/80 (n = 30): Adipocytes from: AGT, Ang II, AT1R, Detected AGT, renin, ACE-1, AT1R and AT2R mRNA expression in adipo- et al. 2002 Obese (BMI > 30); Lean (BMI < 25); abdominal SAT needle biopsy of periumbilical AT2R, renin and cytes but AT2R was barely detectable. [64] biopsy. region. ACE-1 ● Insulin, thyroxine, oestradiol, and Ang II had no significant effect on the Healthy females (n = 4) 34–60 yrs.; BMI 23–31; Mammary SAT. expression of RAS genes studied. breast reduction. Hydrocortisone increased AT1R mRNA expression. (Germany) AGT mRNA expression was significantly lower in obese vs. non-obese. ● Renin, ACE-1 and AT1R mRNA expression was significantly higher in obesity vs. non-obese. Hypertensive obese subjects had the highest AT1R mRNA. Malinowski Patients undergoing surgery for stable isolated Perivascular adipose tissue (PVT) of Ang II PVT significantly decreased the ITA contractility response to serotonin and et al. 2008 coronary artery disease. internal thoracic artery (ITA); Pleural Ang II. [65] (USA) adipose tissue PVT of ITA released nitric oxide (NO) and prostacyclin-independent antic- ontractile factor. Pleural adipose tissue presence did not change the ITA contractility response to serotonin and Ang II. Park et al. 2013 Males (n = 21); SAT and omental VAT. AGT Significantly higher AGT mRNA expression for −20C allele versus −20A [63] Females (n = 24). allele in SAT. (USA) No significant difference in −20C and −20A allele AGT mRNA expression was detected in omental VAT. Prat-Larquemin Females 22–61 yrs. (n = 61); BMI≥28. Mature adipocytes from peri-umbilical SAT AGT Higher levels of AGT secretion in human adipocytes, with greater inter- et al. 2004 (France) needle aspiration individual variation, in comparison to rat adipocytes. [61] AGT secretion was not related to adipocyte size, BMI, blood pressure or M235T AGT gene polymorphism. Adipocyte size differed among AGT genotypes. Sarzani et al. Consecutive patients undergoing radical Visceral adipose tissue (VAT). AGT AGT promotor variants −175 and −163 expressed higher levels of AGT mRNA 2010 [62] nephrectomy (n = 35). in perirenal VAT than tissue from kidney cortex or kidney medulla. Mean: 64.6-yr-old; BMI 27.3 (Italy) Serazin et al. Males (57 ± 8.5 yrs.); BMI 26.2 ± 3.2 (n = 4). SAT fragments AGT Increased adipocyte AGT expression and secretion by cAMP suggested the 2004 [60] (France) sympathetic nervous system may have a role in the activation of the local RAS. cAMP increased the expression and secretion of human AGT in SAT. 16 R. TING ET AL. Many molecular mechanisms operating within adipo- [46] One study found that AGT secretion by SAT cytes have been suggested as possible regulators of human adipocytes was not associated with increased inflammation, including ER stress, hypoxia and cellular blood pressure [61]. Additionally, Ang II reduced thor- senescence. acic ring contraction through the release of NO in Adipose RAS has been shown to play a role in perivascular adipose tissue [34,65]. Another study adipose tissue inflammation. Local administration of found that hypertension was associated with lower Ang II induced tissue hypoxia and increased the levels of AGT and higher levels of renin, ACE-1 and expression of inflammatory markers [45]. Both insulin AT1R mRNA expression in SAT [64]; the inconsistent and TNF-α increased the secretion of AGT and Ang II findings among these studies have been attributed to secretion by adipocytes [46]. In preadipocytes, exposure differences in study population to Ang II increased mitochondrial ROS and increased markers associated with senescence [49]. In adipocytes, 4.5. Strengths and limitations of the study Ang II exposure was shown to increase ER stress and increase levels of NF-κB and its downstream target IL-6 The review applied a systematic and rigorous search [47]. Ang II could also stimulate the release of pro- strategy to retrieve relevant articles according to the thrombotic plasminogen activator inhibitor-1 (PAI-1) research objectives. We used a scoping review to iden- [50]. The undesirable effects of Ang II were inhibited tify the nature and breadth of the current evidence by treatment with ARBs, which indicated that the pro- available. An assessment of the quality of the included inflammatory pathways were associated with Ang II studies is not the usual expectation of scoping reviews interaction with AT1R [47–51]. Additionally, one and thus was not included, which is a potential limita- study found that treatment with ARB reduced inflam- tion of our study. However, we selected only peer- matory markers secreted by mesenteric adipose tissue reviewed primary literature as part of our screening from patients with Crohn’s disease [52]. criteria. Our study summarizes scientific findings and Conversely, ACE-2 has been associated with an anti- highlights significant heterogeneity in several areas inflammatory role. Patients with higher levels of ACE-2 including adipose tissue source and variations in the in epicardial tissue had a lower risk of inflammation- methodology used to characterize adipose RAS. It iden- related issues [58]. Another study associated the reduc- tifies literature gaps and suggests some directions for tion in ACE-2 cleavage in SAT with the anti- future research initiatives on human adipose RAS. inflammatory effects of irisin [57]. Furthermore, ACE- A major limitation of our study was that our data- 2 enzyme can convert Ang II to Ang(1–7) [41]. The base search was conducted on 24 June 2020. Our study Ang(1–7)/MasR pathway has been associated with the showed the state of research available at an early stage counter-regulation of AngII/AT1R [41]. Thus, an of the pandemic. Thus, it would be informative in increase in conversion of Ang II to Ang (1–7) could a future study to compare our study with the state of have the potential to reduce inflammation. research currently available as the pandemic has pro- gressed. Our study was also limited to articles published in the English language. Owing to the broad scope of 4.4. RAS components associated with blood study methodologies used to analyse adipose tissue, the pressure database search strategy was limited by including only Systemic RAS is important for blood pressure control. studies with the term ‘in vitro’ in the MESH heading Various components of human adipose RAS have been used in the search strategy. Furthermore, the COVID- studied for their possible role in systemic blood pres- 19 pandemic has generated a new interest in adipose sure regulation. AGT is a precursor of Ang II, the ACE-2, and there has been an escalation in publica- principal effector hormone for blood pressure regula- tions. Although this scoping review does not capture all tion. A number of studies have investigated the role of articles due to this recent rapid acceleration, it does adipose AGT for blood pressure regulation in humans. serve as a landmark of current information, and has Sympathetic stimulation of adipocytes from SAT with the potential to become a reference point for future a cAMP analogue was shown to increase AGT gene investigations in this area. expression [60]. However, there were many variables associated with AGT gene expression, which included 5. Conclusions a wide inter-individual as well as tissue-specific varia- bility [59,61,62,64,64]. Harte et al. found Ang II that This scoping review was conducted as a preliminary was produced locally in abdominal SAT and was assessment of the state of the literature published a significant source of Ang II in the systemic circulation related to in vitro human adipose RAS from 2001 to ADIPOCYTE 17 2021. 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Journal

AdipocyteTaylor & Francis

Published: Dec 31, 2023

Keywords: Renin-angiotensin system; adipose tissue; human; in vitro studies

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