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

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.