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

Br J Pharmacol. 2015 Aug;172(15):3764-78. doi: 10.1111/bph.13172. Epub 2015 Jun 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism*
  • Angiotensin II / analogs & derivatives
  • Angiotensin II / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Benzimidazoles / antagonists & inhibitors
  • Benzimidazoles / pharmacology
  • Benzoates / antagonists & inhibitors
  • Benzoates / pharmacology
  • Diet / adverse effects*
  • Energy Intake / drug effects
  • Energy Metabolism / drug effects
  • Insulin Resistance / genetics
  • Leptin / pharmacology
  • Male
  • Obesity / drug therapy*
  • Obesity / etiology*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Proto-Oncogene Proteins / agonists*
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Telmisartan
  • Weight Gain / drug effects*
  • Weight Loss / drug effects

Substances

  • 7-Ala-angiotensin (1-7)
  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Benzoates
  • Leptin
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1
  • Angiotensin II
  • Angiotensin I
  • angiotensin I (1-7)
  • Telmisartan