the renin–angiotensin system in adipose tissue and its metabolic consequences during obesity

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Journal of Nutritional Biochemistry 24 (2013) 2003–2015

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The renin–angiotensin system in adipose tissue and its metabolic consequencesduring obesity

Maria E. Frigoleta, Nimbe Torresb, Armando R. Tovarb,⁎

aMount Sinai Hospital, Toronto, ON, Canada M5G1XbInstituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 1Dept. Fisiología de la Nutrición, México, D.F. 14000, México

Received 19 February 2013; received in revised form 24 May 2013; accepted 22 July 2013

Abstract

Obesity is a worldwide disease that is accompanied by several metabolic abnormalities such as hypertension, hyperglycemia and dyslipidemia. Theaccelerated adipose tissue growth and fat cell hypertrophy during the onset of obesity precedes adipocyte dysfunction. One of the features of adipocytedysfunction is dysregulated adipokine secretion, which leads to an imbalance of pro-inflammatory, pro-atherogenic versus anti-inflammatory, insulin-sensitizingadipokines. The production of renin–angiotensin system (RAS) components by adipocytes is exacerbated during obesity, contributing to the systemic RAS and itsconsequences. Increased adipose tissue RAS has been described in various models of diet-induced obesity (DIO) including fructose and high-fat feeding. Up-regulation of the adipose RAS by DIO promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling, all of whichworsen the adipose environment. Consequently, the increase of circulating RAS, for which adipose tissue is partially responsible, represents a link betweenhypertension, insulin resistance in diabetes and inflammation during obesity. However, other nutrients and food components such as soy protein attenuateadipose RAS, decrease adiposity, and improve adipocyte functionality. Here, we review the molecular mechanisms by which adipose RAS modulates systemicRAS and how it is enhanced in obesity, which will explain the simultaneous development of metabolic syndrome alterations. Finally, dietary interventionsthat prevent obesity and adipocyte dysfunction will maintain normal RAS concentrations and effects, thus preventing metabolic diseases that are associated withRAS enhancement.© 2013 Elsevier Inc. All rights reserved.

Keywords: Adipose tissue; Renin–angiotensin system; Diet; Adipocyte; Hypertension; Diabetes

1. The classical renin–angiotensin system (RAS)

The enzymatic function of renin was established in 1898 byTigerstedt and Bergman. Since then, the RAS has been extensivelystudied, and various hormones and receptors are now recognized asplayers in this system [1]. Therefore, multiple effects of the systemand its regulation at cellular and systemic levels have been described.Because regulation of the RAS influences several levels, every levelshould be independently regulated in harmony with other systems tomaintain homeostasis. The RAS system produces angiotensin II (AngII) from angiotensin I (Ang I) and angiotensinogen (AGT) via reninand angiotensin-converting enzyme (ACE). In the classical pathway,AGT is produced mainly by the liver and is drained to the circulation.Subsequently, AGT is converted into the biologically inactive peptideAng I through the action of renin, which is also released into thebloodstream. Renin is an aspartyl protease that is primarily producedby juxtaglomerular cells in the renal afferent arteriole as preprorenin,which is converted to prorenin and then to active renin [2,3]. Thisenzyme cleaves AGT to release the N-terminal decapeptide Ang I [4].

⁎ Corresponding author. Fax: +52 5556553038.E-mail address: [email protected] (A.R. Tovar).

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Then ACE, a peptidyldipeptide hydrolase located in vascularendothelial cells, separates the C-terminal dipeptide from angioten-sin I to produce the octapeptide Ang II [5]. Additionally, ACEmetabolizes the vasodilator bradykinin and inactivates it [6]. Forthese reasons, ACE has a dual role of increasing vasoconstriction andinactivating vasodilation.

The main effector hormone of the system is Ang II, which binds tothe Ang II type 1 (AT1), and Ang II type 2 (AT2) G-protein coupledreceptors to exert its biological functions. AT1 interacts with multipleheterotrimeric G proteins to produce second messengers such asinositol trisphosphate, diacylglycerol and reactive oxygen species [7].Although other roles have been described for Ang II, most of thepathophysiological effects of the hormone are inducedwhen bound toAT1 such as vasoconstriction, increased thirst, aldosterone produc-tion, Na+ reabsorption, nervous sympathetic system activation,hypertrophy and fibrosis [4]. AT2 is the predominant fetal isoform,and its expression is low in most tissues. AT2 mediates its actionsthrough protein tyrosine phosphatase activation, nitric oxide gener-ation, and sphingolipid signaling to stimulate vasodilation, natriure-sis, anti-inflammatory and anti-fibrotic actions [8,9]. Thus, AT1 andAT2 receptors have opposite functions in several cell types [10]. Theexplanation of AT1 and AT2 functions in adipocytes will be describedin this review.

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Other angiotensin peptides hydrolyzed from AGT also havebiological effects. These are angiotensin 2–8 (Ang III), angiotensin3–8 (Ang IV), and angiotensin-(1–7) [Ang (1–7)]. The peptides Ang IIIand IV can be generated from Ang II degradation at the N-terminal byaminopeptidase (A and M), whereas Ang (1–7) is formed from Ang IIthrough ACE2 [11]. Ang (1–7) acts via the Mas receptor (MasR), andAng IV binds to the AT4 receptor, which is associated with insulin-regulated aminopeptidase (IRAP) (Fig. 1).

It is in the endocrine pathway that Ang II is produced in thecirculation and exerts its biological function in the vasculature or indistinct tissues. However, the RAS is significantly more complex. Todeal with such complexity, the RAS can be divided into the endocrineand local systems. The local RAS is defined by Ang II production fromAGT and locally synthesized enzymes [12]. Because AGT is a secretoryprotein, Ang II could be produced inside the cell or in the interstitialspace; consequently, the hormone could be bound to its receptor inneighboring cells, thus acting in an autocrine or paracrine manner[13]. Local Ang II production relies on additional enzymes such astonin, D and G cathepsin and chymase. For example, chymaseconverts 90% of Ang I to Ang II in myocardial extracts [14,15]. Inaddition, cultured skeletal muscle fibers and myoblasts lack reninmRNA, while cathepsin D is expressed during stretching when RAScomponents are up-regulated [16]. Other tissues that have beendescribed to contain the local RAS are the kidney, pancreas, heart,adipose tissue, muscle, liver, adrenal glands and bone marrow[17–20]. Thus, the local RAS in distinct tissues acts via autocrineand paracrine mechanisms to exacerbate the effects of circulatingRAS and/or works independently to induce a response within atissue or cell type.

Fig. 1. The RAS. The classical RAS comprises a series of steps that take place in the circulation. Tpotent enzyme. Ang I is cleaved into Ang II by the ACE. This same enzyme inactivates the vasoblood pressure acting as a vasoconstrictor. The actions of Ang II are mediated by two receptors:peptides derived from Ang II, which include Ang III and Ang IV. These are synthesized by aminoaction of ACE2. The receptor for Ang IV is AT4, which is bound to IRAP in the plasma membbloodstream and tissues, cathepsins and chymase catalyze the production of Ang II locally in vred, and the RAS local enzymes in orange. Angiotensin II and other angiotensin peptides caadipocyte. PRR: prorenin receptor; AT4: angiotensin receptor type IV.

2. The local RAS in adipocytes and its metabolic role

Adipose tissue has recently been described as an endocrineorgan with a great impact on energy metabolism. Thus, adipocytehomeostasis is required to maintain the equilibrium betweennutrient utilization and storage. Adipocyte functions includebalanced hormonal secretion, sensing hormones and other signals,performing lipogenesis and lipolysis at equilibrium, and normaladipocyte growth and development. Other general adipocytefunctions are metabolic processes such as angiogenesis, extracellu-lar matrix reformation, steroid metabolism, immune responses andhemostasis [21].

Additionally, recent findings demonstrate that human and rodentadipose tissues also contain all of the RAS components. AGTmessenger RNA (mRNA) expression has been demonstrated in ratwhite and brown adipose tissue, although greater gene expression isfound in white adipose tissue. Because adipose tissue contains severalcell types aside from adipocytes such as preadipocytes, monocytes,macrophages, vascular stromal cells, nerve cells and fibroblasts, itbecame essential to determine whether adipocytes were responsiblefor adipose tissue AGT or other RAS component production. Severalreports demonstrate that isolated adipocytes from humans [22] androdents [23] as well as the white adipocyte cell line 3T3-L1 allsynthesize AGT [24]. Adipose tissue is a major contributor ofextrahepatic AGT, particularly in obesity [25,26], and AGT mRNAexpression is higher in human visceral adipose depots thansubcutaneous adipose depots [27]. Accordingly, production of AGTin adipose tissue (especially in visceral adipose tissue) in obeseindividuals increases circulating AGT levels as a precursor that can be

he precursor AGT is converted to Ang I through renin, which bound to the PRR is a moredilator bradykinin. Ang II is typically the effector hormone of the system and regulatesAT1 and AT2, which usually have opposing effects. The novel RAS comprises angiotensinpeptidase A andM, respectively. Ang II is also a precursor of Ang(1–7), produced by therane, and the receptor for Ang (1–7) is Mas. Apart from renin and ACE found in thearious tissues. Note that the classical RAS is represented in black text, the novel RAS inn bind their receptors (AT1, AT2, MasR, and AT4) in several cell types including the

2005M.E. Frigolet et al. / Journal of Nutritional Biochemistry 24 (2013) 2003–2015

cleaved by systemic RAS enzymes to produce Ang II and otherangiotensin peptides (Fig. 2).

Other components of the RAS needed for Ang II synthesis andresponsiveness have also been found in adipocytes [24]. For instance,ACE mRNA was present in both subcutaneous and visceral adiposetissue, and in situ hybridization demonstrated gene expression inadipocytes [28]. Although adipocyte renin mRNA expression was notdetectable according to some studies, it has been found ininterscapular brown adipose tissue, and renin activity has beendemonstrated in white and brown adipose tissue as well as 3T3-L1adipocytes [29–31]. However, adipocyte renin activity is relativelylow; therefore, ACE inhibitors do not have direct effects on adipocytes[32]. Determination of low renin activity levels in adipocytes could bedue to decreased renin receptor production because renin and pro-renin bind to their receptors and enhance renin enzymatic activity,which is accompanied by increased Ang II generation [4]. Reninreceptors have been found in human adipose tissue with greaterexpression in visceral compared with subcutaneous adipose tissue[33]. Although renin receptors aremainly located in the adipose tissuestromal vascular fraction, adipocytes also express these receptors[34,35]. Therefore, renin-dependent formation of angiotensin pep-tides is locally modulated by renin receptors in adipocytes and couldpossibly contribute to systemic Ang II concentrations.

As a local system, Ang II production from adipocyte AGT can alsobe achieved through the action of cathepsin isoforms D and G [36,37]and chymase [37], thereby bypassing renin and ACE [36]. Thus,AGT synthesis is a key regulatory step of the RAS in adipose tissuebecause it is present in the vasculature [38]. Additionally, cathepsins

Fig. 2. Nutrients and food components influence the adipocyte local and circulating RAS. HFD,and obesity. AGT and Ang II act locally or are released from the adipocyte into the bloodstreamhypertension and insulin resistance, important components of the metabolic syndrome. In cfunction and preventing metabolic abnormalities.

affect adipocyte biology because they have been associated withpreadipocyte differentiation and adipogenesis and are up-regulatedin obesity [39–41].

Responsiveness to Ang II in adipocytes occurs because of AT1 andAT2 receptor presence. A first study identified Ang receptors as aresult of Ang II binding in rat epidydymal adipocyte membranes [42],and we currently know that rodent and human adipocytes containthese receptors. AT1 receptors have been well described in 3T3-L1and human adipocytes by Western blotting, polymerase chainreaction (PCR), confocal microscopy and binding assays [43–47].Less is known about the biological effects of AT2 receptors, and theexpression of these receptors increases with preadipocyte differen-tiation [47]. Real-time PCR has also confirmed that both rat andhuman adipocytes contain AT2 [48,49]. AT2 is stimulated in certainconditions or when AT1 is blocked because Ang II preferentially actsvia AT2 [50].

Adipocytes and preadipocytes contain the Ang IV and Ang (1–7)receptors, which are AT4-IRAP and MasR, respectively [51]. MasRis a G protein-coupled receptor that is encoded by the Mas proto-oncogene and is related to increased glucose uptake and insulinsensitivity [52–54]. The AT4 receptor associates with membrane-bound IRAP [55]. Interestingly, AT4 could be implicated in insulinsensitivity by binding to angiotensin peptides because IRAPis linked to the glucose transporter glucose transporter 4(GLUT4) [56,57].

With the discovery of the Ang receptor, the autocrine andparacrine activity of the adipocyte RAS was confirmed. Local AGTand Ang II production contribute to circulating concentrations of

sucrose and fructose have shown to induce adipocyte dysfunction, increased local RAS. As a consequence, circulating RAS along with increased leptin and FFA contribute to

ontrast, dietary soy protein and PUFAS decrease adipocyte RAS maintaining adipocyte


these peptides and hence participate in vascular function and bloodpressure regulation in humans. However, AGT could also be releasedand used by adipose tissue as a precursor for Ang II and otherangiotensin peptide production, which can affect the adipocytes andother neighboring cells. It needs to be determined whether the localadipose tissue RAS works independently of the circulating RAS.Adipose tissue renin does not correlate with plasma enzymeconcentrations, as has been shown for cardiac renin [58]. However,adipocyte-generated AGT represents approximately 30% of circulat-ing levels in rodents [59–61]. Moreover, adipose tissue RAS isincreased during the development of metabolic abnormalities suchas obesity, and adipose tissue-secreted AGT is increased in obesehumans and correlates with AGT plasma levels in mice [62]. Excessbody fat, particularly visceral fat, is associated with hypertension andother abnormalities; therefore, adipose tissue RAS could contribute tosystemic RAS in pathophysiological but not regular conditions.Likewise, nutrients can modulate RAS component expression andactivity in adipocytes, adding to whole body RAS and its conse-quences. In further studies, proper techniques should be used todissect local from systemic RAS in physiological, pathological anddiverse nutritional conditions to demonstrate the importance of eachtissue in the total system (Fig. 2).

Conversely, adipose tissue-derived RAS impacts not only circula-tion but also neighboring tissues. Adipocytes within the perivascularadipose tissue secrete RAS components and produce adipokines inresponse to locally generated Ang II, all of which influence vascularfunction [63–65]. The perivascular tissue in aorta and mesentericarteries is mainly brown and white adipose tissue, respectively.Interestingly, Ang II levels were higher in rat mesenteric than in aorticperivascular tissue [66], suggesting differences in local brown andwhite adipose tissue RAS as well as different expression levels of RASmolecules in distinct anatomical regions. In this case, crosstalkbetween adipocytes and vascular cells could explain the mechanisticlink between obesity, insulin resistance, endothelial dysfunction, andhypertension. Furthermore, visceral adipose tissue is the main playerin the development of obesity-associated metabolic abnormalities, incontrast to subcutaneous adipose tissue. Human visceral adiposetissue consistently exhibits significantly elevated AGT mRNA com-pared with subcutaneous adipose tissue [67]. The latter fact explainswhy visceral adiposity is clinically related to hypertension and insulinresistance [68,69].

Although the concept of adipocyte dysfunction is still beingdebated, scientists have thoroughly explored adipocyte physiology inrecent years. In obesity, adipocyte dysfunction has been associatedwith increased pro-atherogenic, pro-diabetic and pro-inflammatoryhormone secretion, which is accompanied by reduced adiponectinrelease [70]. Resistance to hormones such as insulin and leptininfluence adipocyte development. The inability to recruit preadipo-cytes when more mature adipocytes are needed to buffer excess fuelcauses adipocyte hyperthrophy. Larger fat cells release more fattyacids, which in turn increases macrophages in adipose tissue andworsens adipose tissue inflammation [71]. Consequences of adipocytedysfunction comprise obesity-associated abnormalities such asdiabetes, hypertension, cardiovascular diseases, sexual dysfunctionand cancers.

In addition, because adipocyte dysfunction includes imbalancedhormone secretion, increased AGT and other RAS componentproduction could be considered to be a feature of impaired adipocytefunction and is associated with several metabolic abnormalities suchas insulin resistance and hypertension [72]. In this review, we willdiscuss how RAS is associated with glucose and lipid metabolism inthe adipocytes, its involvement in adipose tissue inflammation andthe relationship between the exacerbation of local adipocyte RAS andconcomitant metabolic consequences during obesity as well as itsregulation by nutrients.

3. RAS and glucose metabolism in adipocytes

Increased RAS activity has been associated with insulin resistanceand decreased glucose uptake in various tissues, including adiposetissue. Ang II infusion in the subcutaneous abdominal adipose tissueof healthymen decreased glucose uptake in a dose-dependent fashion[73]. These Ang II effects are possibly mediated by receptor AT1because AT1a-deficient mice maintained insulin sensitivity andincreased energy expenditure after being fed a high-fat diet (HFD)[74]. Ang II receptor blockers (ARB) such as candesartan increaseadipose tissue and skeletal muscle glucose uptake in type 2 diabeticKK-A(y) mice [75]. Additionally, whole body and adipose tissueinsulin resistance in obese Zucker rats is improved by acute andchronic AT1 antagonism with irbesartan [76,77]. Modulation of otherRAS components has also been associated with insulin sensitivity. Forinstance, pharmacological or genetic ACE inhibition improves insulinaction on peripheral glucose disposal in animals [78,79] and clinicalinvestigations [80–84]. In addition, renin inhibition by aliskirenincreases glucose tolerance and whole body insulin sensitivity inobese Zucker rats and Ren2 rats, which manifest increased RASactivity [85,86].

Several mechanisms have been addressed to explain the effects ofAng II on insulin resistance; cross talk between Ang II and insulinsignaling is one of these mechanisms. In responsive tissues, Ang IIinduces serine phosphorylation of proteins that are implicated in theinsulin signaling pathway such as the insulin receptor (IR) and insulinreceptor substrate (IRS-1) and reduces insulin-mediated interactionsbetween IRS-1 and the regulatory p85 subunit of phosphatidylinositol3-kinase [87,88]. While tyrosine phosphorylation of these insulinsignaling proteins is necessary for insulin-mediated effects, serinephosphorylation impedes tyrosine phosphorylation of these mole-cules and therefore decreases insulin action [89,90]. Insulin signalingis also impaired by Ang II signaling through its AT1 receptor via JAK/STAT (Janus kinase/signal transducer and activator of transcription)pathway activation, which induces suppressor of cytokine signaling-3(SOCS-3). Also, c-Jun N-terminal kinase (JNK), a negative feedbackregulator of insulin signaling at the level of IRS-1 [91], is up-regulatedby Ang II [92] and increases SOCS-3 [93]. SOCS-3 can bind to tyrosineswithin the IR and hinder its ability to induce IRS isoform tyrosinephosphorylation [94–96]. Moreover, SOCS-3 binds directly to IRS anddrives its proteosomal degradation in an ubiquitin-dependentmechanism [97,98]. Subsequently, Ang II-mediated impairment ofpost-receptor insulin signaling via insulin signaling protein serinephosphorylation and/or SOCS activation decreases GLUT4 transloca-tion to the plasma membrane (Fig. 3).

Ang II also increases aldosterone secretion, which is anotherpromoter of insulin resistance that is secreted in response toadipocyte-derived compounds including aldosterone stimulatingfactors [58]. More recent evidence indicates that aldosterone causesoxidative stress in cultured adipocytes, contributing to adipose tissuedysfunction [99] and systemic insulin resistance.

As previously mentioned, ACE inhibition increases insulin sensi-tivity, which is particularly relevant in adipocytes, where ACEinhibition causes bradykinin accumulation [100,101]. In turn, brady-kinin increases GLUT4 translocation to the plasma membrane incanine adipocytes [102]. Other reports demonstrate that bradykininincreases glucose uptake in rat adipocytes via endothelial nitric oxidesynthase-mediated JNK inhibition, which is a negative regulator ofinsulin signaling [103]. Therefore, ACE inhibition not only decreasesangiotensin peptide production but also increases bradykinin pres-ence in adipocytes and therefore reduces insulin resistance.

Moreover, the insulin-sensitizing nuclear receptor peroxisomeproliferator activated receptor gamma (PPAR-g) is activated bytelmisartan in adipocytes [104], which is an ARB and PPAR-g agonist[105,106]. PPAR-g enhances insulin action by increasing the secretion

Fig. 3. The adipocyte RAS and insulin signaling. Circulating or locally produced Ang II via its AT1 promotes the activation of JNK through increased proinflammatory cytokines, oxidativestress, or Bk cleavage by ACE. Signaling by the JAK/STAT pathway and JNK induction leads to increased SOCS-3 mediated degradation of IRS-1. Also, JNK can directly phosphorylate IRS-1 in serine residues inhibiting tyrosine phosphorylation of IRS-1 and impairing insulin signaling and GLUT4 translocation to the plasma membrane. The antagonism of AT1 improvesinsulin signaling and glucose uptake while increasing PPAR-gamma activity and adiponectin transcription.


of the anti-inflammatory adipokine adiponectin and preadipocytedifferentiation, which increases lipid storage capacity by preventinglipid overload in non-adipose tissues such as skeletal muscle,pancreas and liver [107,108].

Other mechanisms by which Ang II and angiotensin peptidesinfluence insulin action have been recently described. Ang II increasesinflammatory markers [109,110], which have been associated withinsulin signaling impairment. In preadipocytes, Ang II is an additionalstimulus for producingmonocyte chemoattractant protein 1 (MCP-1),which is induced by the proinflammatory cytokine tumor necrosisfactor alpha (TNF-α) through extracellular signal-regulated kinase(ERK) and p38 MAPK (p38 mitogen activated protein kinase)-dependent pathways [111]. Ang II alters adipokine secretion, andAT1 blockers have favorable effects in terms of improving adiponectinproduction in diet-induced obese (DIO) mouse adipose tissue [112].These blockers also increase apelin levels in adipocyte culture, whichis another beneficial adipokine [113]. In contrast with Ang II, Ang(1–7) acts through MasR to prevent diabetes-induced cardiovascu-lar disease [114], and chronic elevation of plasma Ang (1–7) levelsimproves insulin sensitivity and increases adipocyte glucose uptake[115]. It is interesting that angiotensin peptides have divergenteffects; this could even explain some observations related Ang II toinsulin sensitivity versus insulin resistance in adipocytes. Onereport demonstrated that acute Ang II treatment increasedinsulin-stimulated glucose uptake in adipocytes [48] possiblybecause of increased production of Ang (1–7) or other angiotensinpeptides that utilize Ang II as a substrate and have insulin-sensitizing actions. Also, the time of exposure to Ang II could

explain the contrasting effects of the hormone, since AT1 binding ismodified by time and various stimuli. However, whether Ang (1–7)production from Ang II or exposure time are explanation fordifferent conclusions will need to be assessed in the future. Insummary, Ang II alters glucose metabolism and is implicated intype 2 diabetes-associated insulin resistance via distinctmechanisms.

4. RAS, adipogenesis, and lipid metabolism in adipocytes

Adipogenesis refers to the generation of mature adipocytes frompreadipocytes. This process occurs mainly during the late embryonicstage, although adipogenic capacity is maintained throughout thelifetime in all animal species [116]. AGT, renin, cathepsin D, ACE, Ang IIand AT1 expression are all increased during adipogenesis [22,117]. AngII stimulates adipocyte differentiation, which releases arachidonic acidfrom plasmamembrane phospholipids. Arachidonic acid is used by thecyclooxygenase enzyme to synthesize prostacyclin (prostaglandin I2).The latter is a potent and specific paracrine/autocrine effector ofpreadipocyte differentiation, which also reverses Ang II-mediatedvasoconstriction in adipose tissue [118]. In vivo, Ang II-inducedprostacyclin liberation has been demonstrated by microdialysis inepididymal fat pads, which was attributed to adipocytes [119,120]. Inkeeping with this finding, another study demonstrated that Ang IIinduces the adipogenic marker glycerol-3-phosphate dehydrogenase(GPDH) expression. Expression of this marker is abolished by acyclooxygenase inhibitor, indicating the role of prostacyclin in Ang II-induced adipogenesis [121]. This mechanism appears to be dependent


on PPAR-g because prostacyclin and its stable analogue carbaprostacy-clin bind to this nuclear receptor to regulate fatty acid binding proteinand uncoupling protein-2 expression. However, recent evidencesuggests that rather than altering PPAR-g expression, Ang II regulatesadipogenesis through increased ERK1/2-mediated PPAR-g phosphory-lation in human preadipocytes [122]. Additionally, prostacyclin up-regulates the expression of transcription factors that are involved inadipocyte differentiation, such as C/EBP and , via its cell surfacereceptor [123–125].

In co-culture experiments, evidence suggests that Ang II promotespreadipocyte differentiation by AT2 receptor binding and thuscontrolling prostacyclin-mediated adipogenesis [126]. Moreover, ina mouse model of atherosclerosis, AT2 deficiency was associated withdecreased adipocyte number as well as C/EBP and PPAR-g expres-sion [127]. In contrast, AT1 stimulation by Ang II reduced adipocyteconversion, whereas the ARBs telmisartan and irbestartan inducedadipogenesis and simultaneously activated PPAR-g target genes [22].These results indicate that Ang II is involved in adipocyte differen-tiation through AT2 activation but not through AT1 stimulation inadipose tissue. Therefore, the reported controversies regarding theadipogenic or anti-adipogenic [122,128] effects of Ang II in pre-adipocytes could be because of divergent expression of the two Ang IIreceptor isoforms in rodents versus humans, receptor content indistinct fat pads or variable hormone affinity to these receptors incertain conditions. Another possible mechanism explaining theobserved anti-adipogenic effect of Ang II is down-regulation ofinsulin signaling, whichmediates cell proliferation apart from glucosehomeostasis [129]. Finally, because AT2 expression is regulated bygrowth hormones, use of different conditioned media could alsoaccount for the discrepancies among other in vitro studies.

Ang II also influences lipid metabolism and promotes lipogenesis,which is the production of fatty acids and its esterification intotriglycerides. Ang II exposure increases fatty acid synthase (FAS) andGPDH expression and triglyceride accumulation in adipocytes inrodents and humans [46,130]. In addition, perfusion of subcutaneousadipose tissue with Ang II by microdialysis inhibited lipolysis inhealthy volunteers [73]. This antilipolytic effect could be partlydependent on the vasoconstricting ability of Ang II [129]. Ang II-mediated increase in lipogenesis and decrease in lipolysis contributesto adipocyte enlargement. Generation of transgenic mice in whichadipose AGT is overexpressed or restricted to adipose tissuedemonstrated that targeted AGT expression in adipose tissue in-creases body weight, fat mass, FAS activity and fat cell hypertrophycompared with controls. Hypertrophy was accompanied by hypopla-sia because the cell number of adipocytes was reduced in transgenicmice [61]. Thus, adipose-specific AGT as an Ang II precursor influenceslipid metabolism and subsequently increases adipocyte size.

Thus, Ang II increases lipogenesis, adipocyte hypertrophy, andadipocyte differentiation through its distinct receptors AT1 and AT2.While AT1 decreases adipocyte differentiation [131,132], AT2induces adipocyte maturation and adipose tissue hyperplasia.Preadipocyte conversion into mature adipocytes has been associatedwith increased insulin sensitivity because of efficient lipid storage inadipose tissue. Conversely, adipocyte enlargement precedes macro-phage infiltration and adipose tissue inflammation, which impairsinsulin action. Thus, the effects of Ang II on lipid metabolism andadipocyte morphology via AT2 oppose those of AT1, which affectsglucose metabolism. Moreover, AT1 expression in both visceral andsubcutaneous adipose tissue of obese individuals was found to besignificantly increased, although there were no changes in AT1density in adipose tissues of obese Zucker rats versus lean controls[133]. Therefore, the balance between these two receptors variesamong species and during the development of metabolic abnormal-ities and therefore determines adipose tissue developmental fateand homeostasis.

In summary, the exacerbated secretion of Ang II in obesity,contributes to increased fat mass because of fatty acid accumulationand reesterification with inhibition of lipolysis.

5. Angiotensin and adipocyte inflammation

Adipose tissue undergoes inflammation during obesity onset.Recent studies demonstrated increased angiogenic factor and proin-flammatory cytokine production in murine adipose tissue over-expressing adipose AGT [134,135]. Furthermore, silencing of AGT incultured adipocytes decreases the expression of pro-inflammatorymarkers such as interleukin-6, TNF-α, and MCP-1 [136]. Ang IIinduces proinflammatory adipokine release from both pre- andmature adipocytes and possibly from adipose tissue stromal vascularcells through nuclear factor-kappa B (NF-κB) pathway activation[137–139]. The role of AT1 and AT2 receptors on the inflammatoryprocess is still controversial. Telmisartan administration, whichantagonizes AT1, was found to reduce TNF-α expression andmodulate adipose tissue macrophage polarization to an anti-inflam-matory state in high fat-fed mice [140]. The ARB olmesartan alsoreduced proinflammatory cytokine expression in obese KK-Ay mouseadipose tissue [112]. In isolated adipocytes, valsartan decreasedinflammatory signals in mice that were fed a Western (high fat) diet[141]. This evidence suggests that signaling through AT1mediates theinflammatory consequences of Ang II in adipose tissue and adipo-cytes. However, AT2, which regularly exerts contrasting effects toAT1, has also been implicated in adipose tissue inflammation whenAGT is overexpressed [135]. Further studies should focus on clarifyingwhether Ang II signals via AT1 or AT2 or other receptors such as toll-like receptors to promote inflammation.

Inflammatory reactions induce reactive oxygen species, and thereverse is also true [142]. Ang II increases oxidative stress, which isregulated by AT1 receptor activation [143]. Accordingly, data suggesta beneficial effect of ARBs on oxidative stress. In transgenic ratsexpressing human renin and AGT genes as well as in hypertensivesubjects, oxidative stress was normalized by valsartan treatment[144,145]. The production of reactive oxygen species (ROS) and theexpression of nicotinamide adenine dinucleotide phosphate dehy-drogenase oxidase (NADPH ox) subunits from adipose tissue werereduced by olmesartan treatment in rodents. Simultaneously, incultured adipocytes, the ARB olmesartan acted as an antioxidant andimproved adipokine dysregulation [112].

Inflammation causes glucose intolerance, alters lipid metabolismand contributes to the development of metabolic syndrome. Both AngII-mediated increases in inflammation and ROS production play a rolein insulin resistance and hypertension. Therefore, enhancement ofadipose RAS increases the numerous causes of obesity-associatedmetabolic abnormalities through up-regulating inflammation.

6. Nutrients that modulate the adipose tissue RAS

A new era in nutrition science has evolved in which theinteractions among metabolism, the genome and nutrients are usedto develop new therapeutics for prevention and treatment of chronicdiseases. Nutritional status, nutrient distribution, and nutrients per semodulate the RAS expression and activity in various tissues includingadipose tissue. Fasting and feeding affect AGT production. AGTexpression in epididymal white adipose tissue is regulated by foodintake; AGT decreases during fasting and increases upon re-feeding[24]. Modifying normal nutrient distribution with a HFD activates theadipose and systemic RAS components in humans and rodents, andtargeted inhibition of the RAS protects against DIO in animals [38].Finally, nutrients or food components, such as fructose, lipids, and soyprotein, among others, influence tissue and systemic RAS activity. The


next section will describe the mechanisms by which the RAS isaffected by these nutrients.

6.1. Fructose

Along with an increase in total energy, there has been a shift in thetypes of nutrients that are consumed in the Western diet. Fructoseconsumption has increased significantly, largely because of the softdrinks, baked goods, condiments and desserts that are prepared withhigh-fructose corn syrup [146]. Dietary fructose treatment results inhypertension, glucose intolerance and hypertriglyceridemia in ani-mals [146]. This is because fructose feeding exacerbates presence andactivity of the RAS. In rats, the development of hypertension andmetabolic syndrome after 8 weeks of treatment with 60% dietaryfructose was prevented by renin inhibition with aliskiren treatment[147], thus suggesting a role for Ang II production in fructose-inducedmetabolic abnormalities. In a preliminary study, the nonproteolyticactivation of prorenin, which increases Ang II synthesis andcontributes to insulin resistance, was increased in skeletal muscleand adipose tissue of fructose-fed rats [148]. Dietary fructose alsoincreased AT1 expression and density as well as ACE mRNAabundance in the vasculature and cardiac AGT expression [149–151]. Interestingly, NADPH ox activity and contraction effects Ang II inthe aorta were enhanced in fructose-fed rats compared with controls.These responses to fructose feeding were normalized by administra-tion of the ARB losartan, implicating participation of AT1 receptor[152]. AT1 receptor involvement in vascular dysfunction and insulinresistance was confirmed by a study that utilized gene therapy todemonstrate that fructose consumption-induced hypertension andglucose intolerance were prevented by a single neonatal treatmentwith AT1 antisense DNA [153]. In contrast to Ang II actions throughAT1, the effects of Ang (1–7) are beneficial as the peptide reverseshepatic, skeletal muscle and adipose tissue insulin resistance [154]after high-fructose diet consumption.

In adipose tissue, dietary fructose also increases RAS activation.Sprague–Dawley (SD) rats fed a fructose-enriched diet had increasedAT1 but not AGT expression in adipose tissue [155] along withaugmented fat mass and adipocyte size in epididymal fat pads [156].Both temocapril, an ACE inhibitor, and olmesartan treatment restoredadipocyte size and improved insulin signaling. These findings suggestthat adipose RAS plays a role in fructose-induced metabolicabnormalities apart from systemic RAS.

Other sugars such as sucrose also represent a model of DIO;increases in fat pad weight and adipocyte diameter have beenobserved after sucrose consumption [157]. Sucrose-enriched dietsincrease blood pressure (BP) through sympathetic nervous systemactivation and by increasing renin activity and Ang II plasmaconcentrations. AT1 and ACE inhibition decreased the high-sucrosediet-induced BP elevation. Therefore, carbohydrates modify vascu-lar function through different mechanism including activation ofthe RAS.

6.2. Soy protein

The effects of dietary protein have not been as extensivelyexplored as the effects of lipids and carbohydrates. However, ourgroup has demonstrated that a soy protein-enriched diet exertsbeneficial actions in preventing metabolic abnormalities such aswhole body insulin resistance, impaired pancreatic insulin secretion[158], hepatic and skeletal muscle lipotoxicity [159,160] and adiposetissue dysfunction [161] in a rat model of DIO. In addition, evidenceindicates that soy protein prevents metabolic diseases such ashypertension because of the high arginine content and antioxidantactivity that is exhibited by isoflavones [162].

In retroperitoneal adipose tissue (rAT), dietary soy proteinsignificantly reduced AT1 and cathepsin expression with simulta-neous decreases in adipocyte area and in circulating concentrations ofleptin and insulin. Furthermore, isolated adipocytes from rAT releasedlower Ang II concentrations and were more sensitive to insulin-stimulated Akt activation [163].

The mechanism by which soy protein decreases BP and Ang II-derived functions could be explained by the fact that soy protein-derived peptides and amino acids can alter RAS activity. A soy proteinisolate digest produced in vitro by sequential digestion with pepsinand pancreatin effectively suppresses ACE. Peptides from the latterdigestion process with lower molecular masses and higher hydro-phobicities were more potent ACE inhibitors [164]. In vivo studiesthat have investigated the ingestion of soy protein hydrolysate areconsistent with these findings. Inflammation and ACE activity in thehearts of rats that were fed with the hydrolysate were significantlylower than in control animals [165].

Human and animal studies have documented that specific aminoacids such as cysteine, glutathione, glutamate and arginine attenuatehypertension-associated alterations including insulin resistance,altered RAS functions, and oxidative stress [162]. The isoflavonegenistein, which is also present in soy protein isolates, inhibits ACEexpression in serum and the vasculature [166]. These resultsindicate that soy protein gastrointestinal digestion-derived aminoacids, peptides and isoflavones explain modulation of the systemicand tissue RAS and its beneficial consequences to amelioratemetabolic syndrome.

6.3. Lipids

Dietary fat content and consumption of specific lipids modulatethe RAS components. High-fat feeding has been broadly used toinvestigate obesity-induced metabolic consequences as well aspharmacological, genetic, and dietary factors that potentially improvethese consequences. The relationship between HFD and RAS has beenestablished, and certain RAS components that increase blood pressureare increased with HFD consumption.

AGT-deficient rodents gain less weight and AT1 knockout (KO)mice have less body fat than their littermates after a HFD [167,168].HFD ingestion increases BP in conjunction with AGT mRNAabundance in rAT [169,170]. Along with increased BP, a HFDaugments circulating free fatty acids (FFA) and triglycerides[171,172]. Elevations in BP occur subsequent to obesity in HFD-fedrats. The ARB losartan reverses the HFD-induced increase in BP,supporting a role of RAS activation in obesity-associated hypertension[173]. Moreover, aliskiren, irbesartan and captopril, which are renin,AT1 and ACE inhibitors, respectively, reversed HFD-induced weightgain and increased adiposity. The mechanism by which the RASblockade opposes the HFD-mediated increase in adiposity includeslower leptin and higher adiponectin secretion from adipose tissue[174–176]. Other RAS components that are also modified by high-fat feeding include the pro-renin receptor. Post-natal HFD in ratsresults in increases in the number of adipose tissue pro-renin receptorexpressing cells. In addition, a positive relationship was determinedbetween plasma renin activity and pro-renin receptor positivecell density [35]. Taken together, these data suggest that theadipose RAS is exacerbated during HFD, which affects systemicRAS, thus increasing the risk of developing hypertension and relatedco-morbidities.

In non-adipose tissues, a HFD also enhances the RAS, whichcontributes to metabolic alterations. Myocardial AT1, renin, andNF-κB expression were increased but AT2 expression was reduced inHFD-fed rats [171,172]. Simultaneously, inflammatory markers areinduced in the kidneys, pancreas, aorta and liver by a HFD. RASinhibition attenuated this inflammatory process and improved cell


function in normal rats or models of spontaneous hypertension andstreptozotocin-induced diabetes [177–179]. Angiotensin peptidessuch as Ang (1–7) and Ang IV have contrasting effects with thoseof Ang II regarding insulin sensitivity and ROS generation [180]. AHFD and Ang II infusion [181] impair insulin sensitivity more severelyin ACE2 KOmice than inWTmice, whichwas eradicated by Ang (1–7)infusion [182]. Thus, ACE2, which is the enzyme that cleavesAng II into Ang (1–7), protects against HFD-induced insulin resistancein mice.

In addition to the content of fat in the diet, fatty acids can also alterBP and RAS activity. Increased circulating FFAs as a consequence of aHFD increase vascular sympathetic tone and BP through increasedadrenergic stimulation, oxidative stress, and endothelial dysfunction[183]. However, dietary polyunsaturated fatty acids (PUFAs) havebeneficial effects on BP and other pathologies. Gamma-linolenic acid,an omega-6 PUFA, attenuates the development of hypertension inspontaneously hypertensive rats [184]. This effect was accompaniedby lower plasma aldosterone levels and decreased adrenal AT1density and affinity [185]. An omega-3 PUFA-sufficient diet versus anomega-3-deficient diet in Ren-2 rats reduced hypertension bymodulating the RAS [186]. An omega-3 PUFA-enriched post-nataldiet prevented hypertension partly by regulating the intrarenal RAS inrats [187]. Interestingly, Zucker fa/fa rats fed with the conjugatedlinoleic acid (CLA) trans-10, cis-12 maintained decreased adipocytesize, higher circulating adiponectin levels and lower BP. In this model,AGT expression was higher in larger adipocytes, possibly resulting indecreased AGT expression in adipose tissue of obese rats that were fedwith this CLA [188]. Finally, human studies demonstrate thatconsuming 3 g PUFA/day enhances the favorable effects of blockingthe RAS on kidney injury [189].

Other nutritional factors that modulate the RAS include mono-sodium glutamate (MG), sodium, and food-derived peptides. It hasbeen hypothesized that Katsuobushi oligopeptides from the bonitofish (Sarda sarda), which inhibit ACE, could prevent hypertension andinsulin resistance by boosting Bk action on adipocytes [100]. It is notclear whether MG-DIO regulates AT1 activity and signaling becauseMG elevated AT1 protein levels but reduced Ang II affinity to theadipocyte plasma membrane [190]. Nevertheless, high sodium intaketogether with dietary fructose increases BP and AT1 receptormRNA inrat adipose tissue [155]. High sodium intake also increases renal Ang IIand reduces ACE2 and AT2 expression in obese Zucker rats [191]. Also,supplementation with niacin-bound chromium at adequate dosesincreases insulin sensitivity while lowering the RAS activity throughACE inhibition [192]. In the future, research should focus oninvestigating how several foods or nutrients modify BP. For instance,magnesium, vitamin C, milk, lactic acid bacteria, tea, among others aresources with antihypertensive effects [193]. Many of these com-pounds could reduce BP through the modulation of the adipose orother local RAS and therefore, effort should be put on clarifyingsuch mechanisms.

In brief, carbohydrates, fatty acids, protein content and type, aswell as other food components affect whole body and tissue RAScomponents and activity. Therefore, dietary strategies that benefi-cially modulate the RAS are important tools to maintain vascular andtissue homeostasis for preventing obesity-associated hypertensionand other related abnormalities.

7. Molecular links between obesity, hypertension and diabetes:The role of adipose RAS

The obesity epidemic is related to hypertension and metabolicsyndrome in humans [194]. There is evidence that adipose RAS isimportant to associate RAS with hypertension and insulin resistance[195]. Evidence demonstrates that genes associated with the RAS areoverexpressed in visceral adipose tissue of overweight human

subjects, and ACE gene polymorphisms have been connected toobesity incidence [67,196,197]. A study in postmenopausal womendemonstrated that obese women had higher circulating AGT, renin,aldosterone and ACE levels than lean women [198]. Furthermore,studies in rats and humans have documented weight loss with ACEinhibitor administration, suggesting a role for Ang II in weight gain[199,200]. Visceral adipose tissue, which is a main player in metabolicsyndrome, has increased AGT expression compared with subcutane-ous adipose tissue [27]. Therefore, human obesity is a condition inwhich components of the RAS are exacerbated.

Moreover, the high blood AGT levels and hypertension that areobserved in obese patients may be because of increased fat mass [61].In fact, it has recently been demonstrated that adipocyte AGT plays acentral role in the development of hypertension, since mice deficientin adipocyte AGT fed a high fat diet did not develop high BP comparedto wild-type rats fed the same diet [201]. Consequently, systemic andtissue RAS can cause increased renal sodium reabsorption andchanges in pressure natriuresis [202]. Plasma aldosterone levels arehigher in obese subjects compared with lean subjects, and studiesinvolving humans and animals demonstrate that ACE inhibitors offeradvantages to control hypertension in obesity [203,204]. While therole of the RAS in hypertension and obesity has been established, theRAS is also implicated in impaired glucose homeostasis. Subjects onACE inhibitors or ARBs have a lower risk of developing type 2 diabetescompared with individuals on other anti-hypertensive medications[205]. Improvements in insulin sensitivity and glucose metabolismhave also been demonstrated in rats and humans that are treatedwithRAS antagonists [206,207].

Therefore, there is enough clinical evidence describing theassociation between systemic RAS, hypertension and insulin resis-tance. RAS is exacerbated during obesity, thus implicating the localadipose RAS as a molecular link among metabolic syndromecomponents. In genetic obesity or DIO, adipocytes have increasedRAS activity, which is not observed in the liver [208,209]. In rodents,adipose AGT might represent 60% of hepatic levels and couldcontribute to 30% of total circulating AGT levels [210]. Thedysregulated AGT and Ang II production is actually a featureof “dysfunctional adipose tissue”, which has also been called “sickfat” [72]. The autocrine and paracrine actions of adipose Ang IIworsen adipocyte dysfunction, leading to increased secretion ofadipokines as leptin and resistin and decreased production of theanti-inflammatory adipokine adiponectin. Ang II also induces pro-thrombotic factor plasminogen activator inhibitor-1 secretion byhuman adipocytes [211].

Ang II promotes leptin production in human adipocytes throughan AT1 and ERK1/2- dependent pathway [212] and in murineadipocytes via a prostaglandin-independent mechanism [213].Chronic hyperleptinemia promoted vasoconstriction and augmentedBP by increasing sympathetic nervous system activity [214,215]. Inobese mice, leptin infusion increases aldosterone and BP in theabsence of weight loss, indicating that despite leptin resistance,leptin-mediated vascular stimulation persists in obesity [216].Moreover, leptin has promotes ROS generation, which mightcontribute to hypertension [217]. In contrast with leptin, hypoadipo-nectinemia occurs concurrently with obesity and is an independentrisk factor for hypertension [218–220]. ARBs induce adiponectinproduction via PPAR-g activation [221], suggesting that the RAS isinvolved in reducing adiponectin concentration. Nevertheless, adipo-nectin can also improve BP by increasing nitric oxide generation andbioavailability [222,223].

FFA delivery from adipose tissue to the liver stimulates vascularsympathetic tone and increases BP [224]. Increased circulating FFAconcentrations are found in obesity, which have been associated withimpaired insulin signaling [225]. FFA induce AGT transcriptionalactivation [226]. Thus, FFA from accelerated lipolysis promotes BP


elevation through increasing the RAS, although other mechanismshave been proposed. These include alpha (1)-adrenergic stimulation,endothelial dysfunction, and stimulating vascular smooth muscle cellgrowth and remodeling [227].

Glucocorticoids are not adipokines; however, 11 beta-hydroxys-teroid dehydrogenase type 1 (HSD1), which is the enzyme thatgenerates active cortisol from cortisone, is produced by omental fat[228] and other tissues. Recent studies revealed a prolonged half-lifeof cortisol in some patients with essential hypertension [229]. Micewith HSD1 overexpression are hypertensive, with apparent activationof the circulating RAS. These mice develop visceral obesity, insulinresistance, and dyslipidemia [230].

Taken together, overactivation of the adipose RAS is a keymediator of metabolic complications. Future studies on adipose-specific AGT, AT1 and AT2 animal models are needed to dissect theexact role of the adipose RAS on obesity and associated diseasepathogenesis. However, existing evidence indicates that adipocytedysfunction plays an important role. The increased adipose tissue RASfunction and its consequences on lipid and glucose metabolism,inflammation and impaired insulin signaling are evidence of therelationship between clinical hypertension and insulin resistance inobesity. In addition, adipocyte hypertrophy, pro-inflammatory adi-pokine over-secretion and decreased adiponectin production are allfeatures of adipocyte dysfunction, but are also consequences ofexacerbated adipose RAS, which adds to the already increasedadipose and systemic RAS.

Therefore, adipocyte dysfunction could be an early cause of theexacerbated RAS and/or could be a source that maintains and furtherincreases RAS components along with other factors to establishmetabolic syndrome.

8. Conclusions

The RAS is typically known for its biological actions on thecardiovascular system and kidney to promote vasoconstriction andincrease BP. The presence of a functional adipose tissue RAS is nowwell described. Over activation of the adipose RAS modulatesincreases in body weight and fat mass not only in animal studies,but also in clinical trials. When acting in an autocrine and paracrinefashion, this system promotes adipocyte triglyceride storage, adipo-cyte hypertrophy, and triggers pro-inflammatory adipokine secretion.Both AGT and Ang II are adipokines that are released in highconcentrations into the bloodstream during obesity, which signifi-cantly contribute to systemic levels. Thus, adipose RAS exertsendocrine effects that are important in blood pressure regulation,glucose homeostasis and energy balance. Interestingly, exacerbationof the RAS could be a cause, but also an effect of adipocytedysfunction. Therefore, such dysfunction represents an importantintersection linking metabolic disorders.

There is evidence of nutritional modulation of the adipose andsystemic RAS.While fructose and high fat-induced obesity exacerbatethe adipose and systemic RAS as well as the local RAS in other tissues,other food components such as soy protein and PUFAs attenuate RASpeptide expression in adipose tissue. Further research is essential toimprove our current knowledge on how nutrients modulate theadipose RAS. Using animal models with adipose-specific AGT and RAScomponent knockdown or overexpression in future investigationsshould provide evidence related to the interaction between nutri-tional regulation of the adipose RAS and its contribution to thecirculating RAS. Whole body consequences of the influence ofnutrition on adipose RAS will allow us to better understand the roleof this system in human obesity-related hypertension and insulinresistance. Finally, improved knowledge in these areas will lead tonovel therapeutic targets for metabolic syndrome treatment.

Acknowledgments

This work was supported by CONACYT Mexico (grant 154939 toA.R. Tovar). A Postdoctoral Fellowship from CONACYT was granted toM.E. Frigolet.

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the renin–angiotensin system in adipose tissue and its metabolic consequences during obesity

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