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

¹ Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
² Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil
³ Department of Physiology, Universidade Federal de São Paulo, São Paulo, Brazil
⁴ sanofi-aventis, Montpellier, France
⁵ Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
⁶ Department of Renal and Cardiac Remodeling, Institut National de la Santé et de la Recherche Médicale, U858/I2MR, Toulouse Cedex, France
⁷ Université Toulouse III Paul Sabatier, Institut de Médecine Moléculaire de Rangueil, Toulouse, France
⁸ Institut National de la Recherche Agronomique, AgroParisTech, UMR914 Nutrition Physiology and Ingestive Behavior, Paris, France
⁹ Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany

Corresponding author: Dr. João Bosco Pesquero, Departamento de Biofísica, Universidade Federal de São Paulo, Rua Botucatu 862, 04023-062, São Paulo, Brazil. E-mail: jbpesq{at}biofis.epm.br

Abbreviations: B₁^–/–, kinin B₁ receptor knockout mice; LPS, lipopolysaccharide; NF-B, nuclear factor-B; ob/ob, obese mice lacking leptin; SOCS3, suppressor of cytokine signaling-3; TNF-, tumor necrosis factor-

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.

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