Angiotensin-(1–7) Mas-receptor deficiency decreases peroxisome proliferator-activated receptor gamma expression in adipocytes

Abstract

The renin-angiotensin system is an important link between metabolic syndrome and cardiovascular diseases. Besides angiotensin II, other angiotensin peptides such as angiotensin-(1-7), have important biological activities. It has been demonstrated that angiotensin-(1-7), acting through the G protein-coupled receptor encoded by the Mas protooncogene have important actions on the cardiovascular system. However, the role of angiotensin-(1-7)-Mas axis in lipidic profile is not well established. In the present study, the adipocyte metabolism was investigated in wild type and FVB/N Mas-deficient male mice. The gene expression of peroxisome proliferator-activated receptor gamma, acetyl-CoA carboxylase and the amount of fatty acid synthase protein were reduced in the Mas-knockout mice. Serum nonesterified fatty acids of Mas-knockout showed a 50% increase in relation to wild type group. Basal and isoproterenol-stimulated lipolysis was similar between the groups, however, a significant decrease of the glycerol release (lipolytic index) in response to insulin was observed in wild type animals, while no effect of the insulin action was observed in a Mas-knockout group. The data suggest that the lack of angiotensin-(1-7) action through Mas receptor alters the response of adipocytes to insulin action. These effects might be related to decreased expression of PPARγ.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Deletion of the Mas gene in mice abolishes the binding of Ang (1)(2)(3)(4)(5)(6)(7) in mouse kidney as well as abolishes the antidiuretic action of the peptide after an acute water load (Santos et al, 2003b). Many in vivo effects attributed to Ang(1-7) are diminished or absent in Mas-null mouse tissues and organs, providing support for the proposed ligand receptor pairing (Walther et al, 1998;da Costa Goncalves et al, 2007;Fraga-Silva et al, 2008;Santos et al, 2008;Pinheiro et al, 2009;Mario et al, 2012). An evolutionary account of MAS and related GPCRs is presented in an extensive review recently by Bader et al (2014).…”

“…Overexpression of MAS inhibited the expression of the proinflammatory genes. MAS-deficient mice have increased abdominal fat mass, dyslipidemia, increased levels of insulin and leptin, and altered response of adipocytes to insulin Mario et al, 2012). Mas knockout offers protection from salt-induced hypertension (Heringer-Walther et al, 2012) and from ischemia/ reperfusion injury in both kidney and heart Esteban et al, 2009;Zhang et al, 2012).…”

Increasing Angiotensin-(1–7) Levels in the Brain Attenuates Metabolic Syndrome–Related Risks in Fructose-Fed Rats

“…However, genetic deletion of Mas receptor alters glucose and lipid metabolism and the neural control of blood pressure, inducing a state of MetS. [13][14][15] Taken together, these data provide a clear evidence of a protective role of peripheral Ang-(1-7)/Mas receptor axis in the regulation of cardiovascular system and energy metabolism.Our group showed recently that chronic increase in Ang-(1-7) levels in the brain attenuates DOCA-salt hypertension, and that this effect is related to a dramatic beneficial role Abstract-We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), SpragueDawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose.…”

“…However, genetic deletion of Mas receptor alters glucose and lipid metabolism and the neural control of blood pressure, inducing a state of MetS. [13][14][15] Taken together, these data provide a clear evidence of a protective role of peripheral Ang-(1-7)/Mas receptor axis in the regulation of cardiovascular system and energy metabolism.…”

Modulation of the action of insulin by angiotensin-(1–7)

“…Enhanced glucose tolerance, insulin sensitivity and insulin-stimulated glucose uptake in adipocytes, reduced triglyceridaemia, cholesterolaemia and abdominal fat mass [161], down-regulation of hepatic gluconeogenesis [162], and resistance to high-fat diet with transgenic rats showing increased HDL-cholesterol levels, decreased abdominal fat mass and lower body mass compared with the wild-type animals [163] Acute Ang-(1-7) stimulation in rats Activation of the insulin signalling-related proteins IRS-1, Akt, GSK3 and AS160 via the receptor Mas [88,89,[91][92][93] Ang-(1-7) treatment of adipocytes Improved glucose uptake both in basal and insulin-stimulated states via the Mas receptor and reduced ROS production [132] Deletion of ACE2 in mice Normal insulin sensitivity when fed on a standard diet, but, increased susceptibility to AngII infusion or when fed on a high-fat and high-sucrose diet in terms of the development of glucose intolerance and impairment of insulin sensitivity; this negative effect was eradicated by Ang-(1-7) [167] Overexpression of ACE2 in the pancreas of db/db mice Improved fasting glycaemia, enhanced intraperitoneal glucose tolerance, increased islet insulin content and β-cell proliferation, and reduced β-cell apoptosis; effect eliminated by A-779 [168] Overexpression of ACE2 in AngII-infused mice AngII-infused mice exhibited hyperglycaemia, hyperinsulinaemia and impaired glucose-stimulated insulin secretion from pancreatic islets, decreased ACE2 expression and activity, increased AT 1 R expression, and increased oxidative stress in the pancreas; adenovirus treatment encoding human ACE2 restored pancreatic ACE2 expression, improved β-cell function and restored glucose homoeostasis [169] Mas-KO mice Dyslipidaemia, increased levels of insulin, leptin and abdominal fat mass with normal body mass, glucose intolerance, reduced insulin sensitivity and insulin-stimulated glucose uptake by adipocytes and decreased GLUT4 in adipose tissue [171] Adipocytes from Mas receptor-knockout male mice Altered response of adipocytes to insulin action; effect related to decreased expression of PPARγ [172] Diabetes-induced cardiovascular dysfunction…”