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 B₁ and B₂. 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 B₁ 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 B₁ receptor deficiency in mice (B₁^−/−) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet–induced weight gain. Under high-fat diet, B₁^−/− also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, B₁ receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-B₁^−/−). However, ob/ob-B₁^−/− mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that B₁ receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by B₁ receptor ablation was pharmacologically confirmed by long-term administration of the kinin B₁ receptor antagonist SSR240612 to mice under high-fat diet.

CONCLUSIONS—Our data suggest that kinin B₁ receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity.