Adiponectin is Required to Mediate Rimonabant-Induced Improvement of Insulin Sensitivity but not Body Weight Loss in Diet-Induced Obese Mice
Abstract Number: 100-OR
Authors: STÉPHANIE MIGRENNE, AMÉLIE LACOMBE, ANNE-LAURE LEFEVRE, MARIE-PIERRE PRUNIAUX, ETIENNE GUILLOT, ANNE-MARIE GALZIN, CHRISTOPHE MAGNAN, Paris, France, Rueil-Malmaison, France
Institutions: Paris, France ; Rueil-Malmaison, France
Results: The increase in adiponectin levels in obese patients with untreated dyslipidemia (RIO-Lipid) and mRNA expression in adipose tissue of obese animals was 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 effect of rimonabant in adiponectin knock-out mice (Ad-/-) submitted to diet-induced obesity conditions. To that end, 6 week old Ad-/- male mice and their wild-type littermate controls (C57BL/6 mice, Ad+/+), were fed a high fat diet (72% fat) for 7 months. During the last month, animals were administered daily either with vehicle or rimonabant (10 mg/kg bw) per os. The effects of rimonabant on body weight and food intake were monitored weekly. Glucose turnover rate and insulin sensitivity were also assessed during euglycemic-hyperinsulinemic clamp (6.6 mU/kg/min).
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+/+ (13.3 % ± 1.2%) and Ad-/- (12.9 % ± 0.5%) mice compared to vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad+/+ mice compared to Ad+/+ vehicle-treated mice (glucose infusion rate, GIR: 45 ± 5 vs 30 ± 4 mg/min/kg in vehicle, p<0.05). In contrast, rimonabant failed to improve insulin sensitivity in Ad-/- mice, despite the loss in body weight, (GIR= 28 ± 4 vs 33 ± 1 mg/min/kg in Ad-/- vehicle, ns). To conclude, rimonabant effect on body weight seems independent of adiponectin, whereas adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.