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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 5-11

Role of renin–angiotensin system in obesity associated disorders


1 Obesity Research Center, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
2 Obesity Research Center, College of Medicine, King Saud University, Riyadh; Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia

Date of Submission26-Jun-2018
Date of Decision27-Jun-2018
Date of Acceptance06-Jul-2018
Date of Web Publication13-Mar-2020

Correspondence Address:
Dr. Rukhsana Gul
Obesity Research Center, College of Medicine, King Saud University, PO Box 2925, Riyadh 11461
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjo.sjo_15_18

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  Abstract 


Activation of renin–angiotensin system (RAS) plays a key role in the maintenance of blood pressure, fluid, and electrolyte homeostasis through the action of the vasoactive peptide angiotensin II (Ang II). RAS has now been recognized to play an important role in metabolic diseases. Evidence from both animal and clinical studies suggest that blockade of RAS by reducing the synthesis of Ang II or its binding to angiotensin type 1 receptor (AT1R) via angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prevents the activation of inflammatory signaling mechanism involved in obesity-associated metabolic disorders. Conversely, angiotensin converting enzyme 2 (ACE2)/Ang-(1–7)/Mas receptor (MasR) axis has been proposed as counter regulatory arm with effects opposite to those produced by ACE/Ang II/AT1R. This review summarizes the relevant studies enlightening the role of RAS in obesity-associated disorders with emphasis on the inhibitory effect of ACEi and ARBs on ACE/Ang II/AT1R and stimulation of ACE2/Ang-(1–7)/MasR axis in obesity.

Keywords: ACE, Ang II, ARBs, insulin resistance, obesity, RAS


How to cite this article:
Gul R, Dekhil H, Alfadda AA. Role of renin–angiotensin system in obesity associated disorders. Saudi J Obesity 2018;6:5-11

How to cite this URL:
Gul R, Dekhil H, Alfadda AA. Role of renin–angiotensin system in obesity associated disorders. Saudi J Obesity [serial online] 2018 [cited 2020 Jun 5];6:5-11. Available from: http://www.saudijobesity.com/text.asp?2018/6/1/5/280263




  Introduction Top


The renin–angiotensin system (RAS) plays an essential physiological role in regulating cardiovascular system homeostasis, maintaining hydroelectrolyte balance, blood pressure, and arterial tone besides controlling the growth and differentiation of vascular smooth muscle cells and cardiomyocytes.[1],[2] In contrast, chronic activation of the RAS is intrinsically linked with pathogenesis of hypertensive disorders, inflammation, myocardial infarction, insulin resistance, type 2 diabetes mellitus (T2DM), hypertrophy, oxidative stress, fibrosis, and so on.[1],[2],[3] Angiotensinogen (AGT), an alpha-glycoprotein, is a well-known precursor of RAS. Under normal physiological conditions, AGT is mainly released from liver; however, in various pathological conditions, it is also produced by cells in several tissues such as brain, kidney, liver, and adipose.[4],[5] Renin, which is secreted from juxtaglomerular apparatus of the kidney, cleaves AGT to form angiotensin I (Ang I) (decapeptide).[3],[6],[7] Conversion of Ang I into angiotensin II (Ang II) (octapeptide) by angiotensin-converting enzyme (ACE), an enzyme produced by pulmonary and renal endothelial cells that eliminate the C-terminal dipeptide, represents the principal biochemical axis within the cascade.[8] Ang II is a biologically active potent vasoconstrictor and stimulant of aldosterone release and is considered as a potent effector of RAS whose actions are regulated by two G-protein-coupled receptors, angiotensin type 1 receptor (AT1R), and angiotensin type 2 receptor (AT2R).[9],[10] The major physiological and pathophysiological effects of Ang II are mediated by AT1R.[11],[12],[13] The binding of Ang II to AT1R mediates various physiological actions, for example, in cardiovascular system (vasoconstriction, increased blood pressure, increased cardiac contractility), in kidney (inhibition of renin release, renal tubular salt reabsorption), in sympathetic system, and adrenal cortex (eliciting aldosterone synthesis).[13],[14] In pathophysiological condition, overproduction of Ang II mediates various deleterious effects such as hypertrophy, fibrosis, increased cell proliferation, inflammatory responses, and oxidative stress.[15],[16],[17],[18] Contrarily, binding of Ang II to AT2R produces opposite effects compared to those mediated by the AT1R.[19],[20],[21] The complexity of RAS cascade has expanded by recent finding to encompass an alternative counter regulatory axis composed of angiotensin converting enzyme 2 (ACE2)/Ang-(1–7)/Mas receptor (MasR) receptor in addition to its vasoconstrictor/proliferative ACE/Ang II/AT1R axis. Ang-(1–7) (heptapeptide) is an active component of the RAS produced by cleavage of Ang II at C-terminal amino acid phenylalanine by the action of carboxypeptidases, ACE2, which has approximately 400-fold less affinity to Ang I than to Ang II.[21],[22],[23],[24] In addition, C-terminal residue of Ang I is cleaved by the action of ACE2 to produce Ang-(1–9) (nonapeptide), which in turn is converted to Ang-(1–7) by ACE. Ang-(1–7) binds to MasR and has multiple actions that are mostly opposite to those described for Ang II such as vasodilatation, antiproliferative, antihypertrophic, and antifibrotic effects.[25],[26] The RAS overactivation is linked to the progression of obesity-associated disorders. Accumulating evidences suggest that interruption of ACE/Ang II/AT1R axis by ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) or eliciting the activity of ACE2/Ang-(1–7)/MasR axis may work as an effective strategy to treat obesity and its comorbidities as discussed below.


  Materials and methods Top


PubMed, Scopus, Google Scholar, and Science Direct database were searched using keywords RAS and Obesity to find the pertinent material for this review from the period of September 2017 to March 2018 by R.G. The material was collected from peer-reviewed original manuscripts, review articles, and meta-analyses. The key focus of this review is the role of RAS in obesity and its comorbidities. The review also assessed the effect of ACE/Ang II/AT1R axis blockade and ACE2/Ang-(1–7)/MasR axis stimulation on obesity.


  RENIN–ANGIOTENSIN SYSTEM AND OBESITY Top


Obesity is known to stimulate tissue RAS and vice versa.[27] Increase in fat mass is associated with overactivation of RAS in rodents and humans.[28] Adipose tissue expresses all of the components of RAS, that include AGT, renin, ACE, and ACE2, and locally produce Ang II and other angiotensin peptides.[28] AGT is significantly produced in adipose tissue and is constitutively released by adipocytes in animal models and humans.[29] In addition, both preadipocytes and mature adipocytes express both AT1R and AT2R as well as receptors for Ang IV and Ang-(1–7).[30] The role of RAS in obesity is evident from the fact that weight loss in an individual is accompanied by reduction in adipose tissue mass and systemic RAS activity.[31],[32] Recent studies have revealed an increased systemic and adipose tissue RAS activation in obese patients, and the activation was found to be higher in visceral or central adipose tissue compared to the subcutaneous tissue.[33] Moreover, in genetic models of obesity such as ob/ob and db/db mice, both systemic and adipose RAS are overactivated.[34]

Blockade of RAS has been suggested to reduce obesity.[35],[36] Several pharmacological and genetic modifications of RAS in animals have provided extensive data confirming a pivotal role of the RAS in body weight regulation.[37] ARBs have been found to reduce body weight in both rodents and humans patients.[38],[39],[40],[41],[42],[43] Evidences suggest that treatment with ACEi or ARBs or knock down of any of the key components of RAS leads to weight loss.[39],[40],[44],[45],[46],[47],[48] Similarly, mice lacking renin or ACE have also been found to be protected from fat mass expansion.[39],[45] The reduction in fat mass in the RAS knockout mice is not linked to decreased food intake but with the increase in metabolic rate in these animals.[39],[40],[45],[46],[49]

AGT knockout mice exhibit a lower adiposity compared to wild type, whereas on the other hand, overexpression of AGT levels in transgenic mice or overexpression of AGT in adipose tissue causes an increase in adiposity. Similarly, mice lacking AT1R are protected against diet-induced obesity, indicating a role of AT1R signaling in obesity.[40],[45],[46],[47],[48],[49],[50] In addition, Ang II levels are significantly higher in both humans and rodents with genetic or diet-induced obesity.[34],[50],[51] Clinical trials suggest that blockade of RAS by reducing the synthesis or action of Ang II via pharmacological inhibitors prevents obesity-associated metabolic disorders like insulin resistance. Moreover, some animal studies have demonstrated that reducing Ang II levels by ARBs negatively influences adiposity indicating Ang II acts in an endocrine manner in the development of obesity. These findings support that RAS activity directly correlates with body weight and adiposity.

Unexpectedly, Cassis et al.[52] have demonstrated that overactivation of systemic RAS by Ang II infusion leads to sustained reduction in weigh rather than weight gain, which may be contributed to increased energy expenditure. Similarly, Marijke et al. have shown that Ang II infusion in hypertensive rats reduced the body weight by 18% to 26% within a week, which is attributed to decrease in food intake, and these changes in body weight were inhibited by blocking AT1R.[53] Furthermore, recently chronic Ang II infusion in rats has been shown to significantly prevent the development of obesity when compared to Ang-(1–7) treatment. It is apparent from these studies that increase in systemic Ang II levels reduces obesity and regulates energy homeostasis by decreasing energy intake and increasing its expenditure.[54] These evidences signifying that the antiobesity effect of circulating RAS overactivation is contradictory to the above findings, suggesting RAS overactivation increases adiposity. Further studies are required to understand the inconsistency in these findings.


  ACEI/ARBS IN OBESITY Top


Blockade of the RAS with either ACEi or ARBs plays an important role in preventing Ang-II-related obesity disorders by inhibiting ACE/Ang II/AT1R axis and augmenting the action of ACE2/Ang-(1–7)/MasR axis.[55],[56] Inhibition of ACE by ACEi blocks the conversion of Ang I into Ang II, whereby decreasing systemic and local Ang II levels.[56] In addition, ACEi can also produce its effects by increasing Ang-(1–7) as a consequence of increased renin secretion and Ang I, which is main precursor for Ang-(1–7). In spontaneously hypertensive rats, ACEi provokes an increase in plasma and tissue levels of Ang-(1–7),[57] which might attribute to antihypertensive effect of ACEi. Treatment with ACEi also reduces body weight and food intake.[42],[58],[59] ACE inhibition by enalapril administration in animals exhibited a decrease in energy intake and leptin levels. In addition, treatment of normotensive rats with enalapril in the presence of a normal standard hyperlipidic diet decreases body fat with no changes in serum lipid profile.[42] Both ACEi and ARBs improve insulin sensitivity and glucose intolerance by increasing glucose uptake in skeletal muscle via GLUT-4 translocation to membrane.[57] ARBs like telmisartin have also been shown to increase glucose uptake and increase insulin sensitivity both in vitro and in vivo. Furthermore, telmisartan has also been shown to prevent lipogenesis and weight gain through the activation of PPAR-δ pathways in adipose tissue.[61],[62]

Several clinical studies have suggested that in hypertensive patients, RAS inhibition by ACEi or ARB delays the onset of T2DM.[63],[64] Moreover, multiple meta-analyses have demonstrated 22% to 30% decreases in the prevalence of T2DM by treatment with an ACEi or ARB.[65] Treatment with ARB, losartan and ACEi, ramipril increased the levels of adiponectin and improved insulin sensitivity without changing adiposity.[66] In patients with obesity, a decrease in adiponectin levels is known to increase the chances of developing cardiovascular disease, T2DM, and metabolic syndrome. Increase in adiponectin levels and insulin sensitivity by candesartan, ARB and ramipril, ACEi is much higher compared to other antihypertensive drugs like atenolol or thiazide.[67] Blockade of RAS by inhibiting AT1R exhibits decrease in insulin resistance, which in turn decreases the chances of T2DM in prediabetic patients. The improvements in insulin sensitivity by ACEi is assumed partly to be linked to its effect on decreased Ang II production or increased levels of systemic and local Ang-(1–7). Inhibition of ACE by captopril has been shown to improve glucose uptake by increasing the endogenous production of Ang-(1–7) in skeletal muscles.[68] These findings suggest that treatment with ACEi and ARBs besides reducing the adiposity may also decrease the risk of developing T2DM.


  ACE2/ANG-(1–7)/MASR AXIS IN OBESITY Top


The ACE2/Ang-(1–7)/MasR axis is the counter-regulatory arm in the RAS with effects opposite to those produced by ACE/Ang II/AT1R.[69] Ang-(1–7)/MasR axis has been accepted as a new potential tool for the treatment of metabolic diseases by modulating lipid and glucose metabolism. Recent findings have suggested that mice lacking MasR have augmented AGT expression with increased adiposity, glucose intolerance, and decreased insulin sensitivity.[49] Similarly, deficiency of ACE2 resulted in impaired glucose tolerance and insulin resistance in mice fed with high fat diet.[60] In a separate study, genetic deletion of MasR in mice shows reduced expression of adiponectin in tissue and the GLUT-4 in adipose tissue besides other manifestations of metabolic syndrome like dyslipidemia, insulin resistance.[49] High-fat diet in transgenic (TGR) rats with increased Ang-(1–7) expression has been shown to have reduced body fat mass and increased high density lipoprotein (HDL) cholesterol levels, with no changes in energy intake.[70] Transgenic mice with increased Ang-(1–7) in circulation showed an increased insulin sensitivity, glucose tolerance, and uptake with diminished triglyceride and cholesterol levels and body fat mass despite normal food intake.[71] Administration of Ang-(1–7) orally in rats with diet-induced obesity increased glucose tolerance and insulin-sensitivity, and reduced abdominal fat mass, plasma insulin and systemic lipid levels.[72] Studies suggest that Ang-(1–7) plays an important role is regulation ACE/ACE2 ratio. Deoxycorticosterone acetate (DOCA) hypertensive TGR rats with elevated circulating Ang-(1–7) levels showed increased heart Ang-(1–7) levels and decreased ACE messenger RNA (mRNA) expression. On the contrary, ACE inhibition by captopril reduces the gain in body weight via Ang-(1–7) by increasing the expression of MasR.[73] Genetic deletion of MasR in FVB/N mice causes changes in glucose and lipid metabolism leading to a state like metabolic syndrome.[49] These studies suggest that ACE2/Ang-(1–7)/MasR axis might be a novel therapeutic agent for the prevention and treatment of obesity-associated disorders.


  RENIN–ANGIOTENSIN SYSTEM AND INSULIN RESISTANCE Top


Insulin resistance is a state in which insulin-sensitive tissues fail to respond to circulating insulin. Binding of insulin to its receptor autophosphorylates insulin receptors (IRs) intrinsic tyrosine kinases, which in turn phosphorylates IR substrate (IRS)-1, thereby activating cascade of intracellular signaling events and leading to glucose uptake.[71] Failure of pancreatic beta cells to produce insulin to overcome prolonged insulin resistance leads to a pathological state called T2DM. Accumulated evidences mentioned above indicate that RAS blockade by ACEi and ARB increase insulin sensitivity and utilization of glucose.[75] Several clinical trials have also demonstrated that blockade of RAS reduces the risk of developing the T2DM. In the Captopril Primary Prevention Project, a trial evaluating ACEi (captopril) for the primary prevention in hypertensive patients, there was 14% reduction in the risk of developing the diabetes.[74],[75] Moreover, in Heart Outcomes Prevention Evaluation trial evaluating ARB (ramipril), a 34% reduced risk was observed compared to the placebo control group.[76] Genetic deletion of renin, ACE, AT1R, or AT2R shields animals from high-fat-diet-induced obesity and insulin resistance.[39],[45],[47],[77] On the contrary, overactivation of RAS in rodents causes glucose intolerance and reduced insulin sensitivity, further signifying the role of RAS overactivation in the onset of T2DM. Consistently, mice overexpressing renin in the liver (RenTgMK) with elevated levels of systemic renin and Ang I also increase glucose intolerance along with other pathological manifestations.[54] Additional mechanisms contributing to improvement in insulin sensitivity by RAS blockade include the inhibition of bradykinin degradation which in turn also increase glucose uptake. In TG(mREN2)27 rat, a model with overactivated RAS developed whole-body insulin resistance, which was significantly improved by the treatment with either direct renin inhibition or AT1R blockade.[78]Ang II is known to impair insulin signaling by reducing glucose metabolism and decreasing its uptake and utilization. Ang II promotes serine phosphorylation and suppresses tyrosine phosphorylation of IRS-c and subsequent Akt stimulation and translocation of GLUT-4 to membrane, thereby diminishing glucose uptake. Ang-II-mediated activation of AT1R increases reactive oxygen species (ROS) generation via oxidase, nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase activation.[18] Increase in ROS generation activates transcription factor nuclear transcription factor kappa B (NF-κB), which in turn increases transcription of cytokine tumor necrosis factor α (TNFα) and interlukin-6 (IL-6). These cytokines on binding to their receptors increase the activations of suppressor of cytokine signaling (SOCS), Jun N-terminal kinase (JNK), and protein tyrosine phosphate-B (PTP-B), and inhibit insulin signaling. In rodents, Ang II also reduces muscle glucose utilization by decreasing skeletal muscle mitochondrial content conceivably through increased ROS generation. Significantly, many clinical trials have revealed that RAS blockers reduce risk of developing T2DM independent of changes in blood pressure when compared to other blood pressure lowering medications.[79],[80] Patients consuming ACEi for lowering blood pressure have a much lower risk of developing new-onset diabetes when compared to patients using β-blockers to improve vasodilation and decrease blood pressure. In fact, patients using β-blockers have been shown to have increased risk of developing T2DM.[81]


  Conclusion Top


In conclusion, clinical and animal studies suggest that the systemic RAS is overactivated in obesity-associated disorders. Both pharmacological and genetic manipulation of RAS has provided considerable evidence, suggesting a pivotal role of the RAS in body weight regulation and improving insulin sensitivity. Blockade of ACE/Ang II/AT1R axis with ACEi or ARBs represents an effective strategy to treat obesity and its comorbidities. Conversely, stimulating the activity of counter-regulatory arm ACE2/Ang-(1–7)/MasR axis with effects opposite to those produced by ACE/Ang II/AT1R has been implicated in prevention and treatment of obesity-associated disorders.

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Conflicts of interest

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Introduction
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RENIN–ANGI...
ACEI/ARBS IN OBESITY
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