Kinin B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity

OBJECTIVE-Kinins mediate pathophysiological processes related to hypertension, pain, and inflammation through the activation of two G-protein-coupled receptors, named B(1) and B(2). Although these peptides have been related to glucose homeostasis, their effects on energy balance are still unknown.RESEARCH DESIGN and METHODS-Using genetic and pharmacological strategies to abrogate the kinin B(1) receptor in different animal models of obesity, here we present evidence of a novel role for kinins in the regulation of satiety and adiposity.RESULTS-Kinin B(1) receptor deficiency in mice (B(1)(-/-)) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet-induced weight gain. Under high-fat diet, B(1)(-/-) also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, B(1) receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-B(1)(-/-)). However, ob/ob-B(1)(-/-) mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that B(1) receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by B(1) receptor ablation was pharmacologically confirmed by long-term administration of the kinin B(1) receptor antagonist SSR240612 to mice under high-fat diet.CONCLUSIONS-Our data suggest that kinin B(1) receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity. Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, Brazil Univ Mogi das Cruzes, Mogi Das Cruzes, Brazil Universidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, Brazil Sanofi Aventis, Montpellier, France Universidade Federal de São Paulo, Dept Med, BR-04023062 São Paulo, Brazil Inst Natl Sante & Rech Med, Dept Renal & Cardiac Remodeling, U858 I2MR, Toulouse, France Univ Toulouse 3, Inst Med Mol Rangueil, F-31062 Toulouse, France Inst Natl Rech Agron AgroParisTech, UMR914 Nutr Physiol & Ingest Behav, Paris, France Max Delbruck Ctr Mol Med, Berlin, Germany Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, Brazil Universidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, Brazil Universidade Federal de São Paulo, Dept Med, BR-04023062 São Paulo, Brazil Web of Science