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ENDOCRINE PHYSIOLOGY AND METABOLISM

Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

¹University Paris-Diderot, Centre National de la Recherche Scientifique, Paris, France; and ²Sanofi-Aventis Research and Development, Rueil-Malmaison, France

Submitted 9 October 2008 ; accepted in final form 3 February 2009

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad^–/–) exposed to diet-induced obesity conditions. Six-week-old Ad^–/– male mice and their wild-type littermate controls (Ad^+/+) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad^–/– mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad^+/+ and Ad^–/– mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad^+/+ mice compared with Ad^+/+ vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad^–/– mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

endocannabinoid system; cannabinoid receptor 1 antagonist; metabolic syndrome

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