Peroxisome proliferator-activated receptor-gamma (PPARgamma) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPARgamma activation. Administration of the PPARgamma agonist rosiglitazone (15 mg/kg.d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T(4) and T(3)) and mRNA levels of BAT and liver T(3)-generating enzymes iodothyronine type 2 (-40%) and type 1 (-32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms alpha1 (-34%) and beta (-66%) in BAT and isoforms alpha1 (-20%) and alpha2 (-47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPARgamma-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.

The effects of the cannabinoid-1 receptor (CB 1 ) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB 1 antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB 1 antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum-fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB 1 blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB 1 antagonism from exerting beneficial effects on energy and glucose metabolism. Diabetes 55:3403-3410, 2006 O besity results from a prolonged energy imbalance during which intake exceeds expenditure. The difficulty to lose excess weight is tightly linked to the ability of the systems regulating energy balance to defend body weight. The complexity and redundancy within these systems, which involve an intricate network of peripheral signals and neuronal circuits, constitute obstacles to finding potential targets for antiobesity treatments. Currently, one of the most promising targets for the pharmacological treatment of obesity is the cannabinoid-1 receptor (CB 1 ). Rimonabant (SR141716), the first selective CB 1 antagonist (1), acts as a potent antiobesity agent when administered to dietinduced obese mice (2). Rimonabant is presently in phase III clinical trials for the treatment of obesity. The recently published results from clinical trials, known as Rimonabant in Obesity-Europe (3), Rimonabant in ObesityLipids (4), and Rimonabant in Obesity-North America (5), indicate that rimonabant not only reduces body weight but also improves cardiovascular risk factors associated with obesity.The precise mechanism responsible for the antiobesity effect of rimonabant remains unknown. It has been suggested that the hypophagic effect of CB 1 antagonists results from an attenuation of feeding-related reward processes (6,7) that could be under the modulation of hypothalamic centers regulating energy balance. Injection of the endocannabinoid anandamide in the ventromedial hypothalamic nucleus, an area rich in CB 1 mRNA (8), in...

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