ABSTRACT
BACKGROUND AND PURPOSE: Reduced weight gain after treatment with AT1 receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan. METHODS: Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow. SD and TGR(ASrAOGEN) rats on the CD diet were also treated with telmisartan (8 mg·kg(-1) ·d(-1) , 3 months). RESULTS: Compared with SD rats, TGR(ASrAOGEN) rats (i) had lower weights during chow feeding, (ii) did not become obese during CD feeding, (iii) had normal baseline leptin plasma concentrations independent of the feeding regimen, whereas plasma leptin of SD rats was increased due to CD, (iv) showed a reduced energy intake, (v) had a higher, strain-dependent energy expenditure, which is additionally enhanced during CD feeding, (vi) had enhanced mRNA levels of pro-opiomelanocortin and (vii) showed improved glucose control. Weight gain and energy intake in rats fed the CD diet were markedly reduced by telmisartan in SD rats but only to a minor extent in TGR(ASrAOGEN) rats. CONCLUSIONS: The brain renin-angiotensin system affects body weight regulation, feeding behaviour and metabolic disorders. When angiotensin II levels are low in brain, rats are protected from developing diet-induced obesity and obesity-related metabolic impairments. We further suggest that telmisartan at least partly lowers body weight via a CNS-driven mechanism.
Subject(s)
Body Weight/physiology , Diet/adverse effects , Obesity/etiology , Obesity/metabolism , Renin-Angiotensin System/physiology , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacology , Benzoates/administration & dosage , Benzoates/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Male , Rats , Rats, Transgenic , Renin-Angiotensin System/drug effects , TelmisartanABSTRACT
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.
