OBJECTIVE - 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 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 aimed at investigating the effects of rimonabant in adiponectin knock-out mice (Ad^-/-) exposed to diet-induced obesity conditions. RESARCH DESIGN AND METHODS - Six week old Ad^-/- male mice and their wild-type littermate controls (Ad^+/+), were fed a high fat diet for 7 months. During the last month, animals were administered daily either with vehicle or rimonabant per os (10 mg/kg). RESULTS - 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 to vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad^+/+ mice compared to 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. CONCLUSION - Rimonabant effect on body weight appeared independent of adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.