Kinin B1 Receptor Deficiency Leads to Leptin Hypersensitivity and Resistance to Obesity

Abstract 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, we present here 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 (HFD)-induced weight gain. Under HFD, 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 HFD. 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.