In this study, we aimed to establish the mechanisms whereby peroxisome proliferator-activated receptor ␥ (PPAR␥) agonism brings about redistribution of fat toward subcutaneous depots and away from visceral fat. In rats treated with the full PPAR␥ agonist COOH (30 mg ⅐ kg ؊1 ⅐ day ؊1 ) for 3 weeks, subcutaneous fat mass was doubled and that of visceral fat was reduced by 30% relative to untreated rats. Uptake of triglyceride-derived nonesterified fatty acids was greatly increased in subcutaneous fat (14-fold) and less so in visceral fat (4-fold), with a concomitant increase, restricted to subcutaneous fat only, in mRNA levels of the uptake-, retention-, and esterificationpromoting enzymes lipoprotein lipase, aP2, and diacylglycerol acyltransferase 1. Basal lipolysis and fatty acid recycling were stimulated by COOH in both subcutaneous fat and visceral fat, with no frank quantitative depot specificity. The agonist increased mRNA levels of enzymes of fatty acid oxidation and thermogenesis much more strongly in visceral fat than in subcutaneous fat, concomitantly with a stronger elevation in O 2 consumption in the former than in the latter. Mitochondrial biogenesis was stimulated equally in both depots. These findings demonstrate that PPAR␥ agonism redistributes fat by stimulating the lipid uptake and esterification potential in subcutaneous fat, which more than compensates for increased O 2 consumption; conversely, lipid uptake is minimally altered and energy expenditure is greatly increased in visceral fat, with consequent reduction in fat accumulation. Diabetes

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.

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PICARD, FRÉ DÉ RIC, YVES DESHAIES, JOSÉ E LALONDE, PIERRE SAMSON, AND DENIS RICHARD. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res. 2000;8:656 -663. Objective: This study examined the effects of topiramate (TPM), a novel neurotherapeutic agent reported to reduce body weight in humans, on the components of energy balance in female Zucker rats. Research Methods and Procedures: A 2 ϫ 3 factorial experiment was performed in which two cohorts of Zucker rats differing in their phenotype (phenotype: lean, Fa/?; obese, fa/fa) were each divided into three groups defined by the dose of TPM administered (dose: TPM 0, vehicle; TPM 15, 15 mg/kg; TPM 60, 60 mg/kg). Results: The reduction in body weight gain induced by TPM in both lean and obese rats reflected a decrease in total body energy gain, which was more evident in obese than in lean rats. Whereas TPM administration did not influence the intake of digestible energy in lean rats, it induced a reduction in food intake in obese animals. In lean, but not in obese rats, apparent energy expenditure (as calculated by the difference between energy intake and energy gain) was higher in rats treated with TPM than in animals administered the vehicle. The low dose of TPM decreased fat gain (with emphasis on subcutaneous fat) without affecting protein gain, whereas the high dose of the drug induced a reduction in both fat and protein gains. The effects of TPM on muscle and fat depot weights were representative of the global effects of TPM on whole body fat and protein gains. The calculated energetic efficiency (energy gain/energy intake) was decreased in both lean and obese rats after TPM treatment. TPM dose independently reduced hyperinsulinemia of obese rats, but it did not alter insulinemia of lean animals. Discussion: The present results provide sound evidence for the ability of TPM to reduce fat and energy gains through reducing energetic efficiency in both lean and obese Zucker rats.

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...