Lack of weight gain after angiotensin AT₁ receptor blockade in diet‐induced obesity is partly mediated by an angiotensin‐(1–7)/Mas‐dependent pathway

Abstract

Background and Purpose Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin‐(1‐7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin‐(1‐7) has beneficial cardiovascular and metabolic effects. Experimental Approach We investigated the anti‐obesity effects of transgenically overexpressed angiotensin‐(1‐7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg−1·d−1) in diet‐induced obese Sprague Dawley (SD) rats can be blocked when the animals were co‐treated with the Mas receptor antagonist A779 (24 or 72 μg·kg−1·d−1). Key Results In contrast to wild‐type controls, transgenic rats overexpressing angiotensin‐(1‐7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain‐dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan‐induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779. Conclusions and Implications Angiotensin‐(1‐7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin‐(1‐7)‐like agonists may be drug candidates for treating obesity.

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

“…In this regard, Gupte and colleagues observed an increase in ACE2 concentration in adipose tissue of mice, fed with high-fat diet (Gupte et al, 2008). Very recently, it could be shown by members of our group that Ang(1-7) overexpression in rats could antagonize the diet-induced obesity (Schuchard et al, 2015). However, it remained unclear, whether these positive effects are also detectable regarding the cardiovascular performance.…”

“…In this study the working group of Prof. Dr. Raasch, Institute of Experimental and Clinical Pharmacology and Toxicology of the University of Lübeck investigated the effect of cafeteria diet (CD) and an overproduction of Ang(1-7) on metabolic parameters like body weight, food intake and insulin sensitivity at day 147 or 154 as described in the manuscript of Schuchard et al (2015). For measurement of the insulin sensitivity an insulin tolerance test was carried out: 0.6 international units per kg body weight were administered subcutaneously and glucose levels were determined in blood samples during a 360 min period.…”

“…In this transgenic rat model, an Ang(1-7)-producing fusion protein (TGR(A1-7)3292) was expressed in the testis of the rats. This fusion protein is then cleaved in the testis tissue resulting in an about 4.5-fold increase in testicular Ang(1-7) and a 2.5-fold increase in circulating Ang(1-7) (Schuchard et al, 2015). In detail, the generation of these transgenic rats was described previously by Santos et al (2004).…”

“…As previously described, CD consisted of commercial chocolate and cookies (62% carbohydrates, 25% fat, 6% protein, 2% fiber). Rats received only one kind of sweet per day (Müller-Fielitz et al, 2015;Schuchard et al, 2015). Furthermore, chocolate and cookie bars were changed daily in a regular manner (Müller-Fielitz et al, 2015;Schuchard et al, 2015).…”

“…Rats received only one kind of sweet per day (Müller-Fielitz et al, 2015;Schuchard et al, 2015). Furthermore, chocolate and cookie bars were changed daily in a regular manner (Müller-Fielitz et al, 2015;Schuchard et al, 2015). The third group were transgenic (TGR) rats, receiving standard chow food (TGR+chow, n = 6).…”