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Effects of Rimonabant (SR141716) on Fasting-Induced Hypothalamic-Pituitary-Adrenal Axis and Neuronal Activation in Lean and Obese Zucker Rats

From the Merck Frosst/CIHR Research Chair in Obesity and Centre de recherche de l’Hôpital Laval, Hôpital Laval, Québec, Canada

Address correspondence and reprint requests to Denis Richard, Direction de la recherche, Hôpital Laval, 2725 chemin Sainte-Foy, Québec, Québec, Canada, G1V 4G5. E-mail: denis.richard{at}crhl.ulaval.ca

Abbreviations: AgRP, agouti-related peptide; ARC, arcuate nucleus; BAT, brown adipose tissue; CB₁, cannabinoid-1 receptor; CRF, corticotropin-releasing factor; HOMA-IR, homeostasis model assessment of insulin resistance; HPA, hypothalamic-pituitary-adrenal; MCH, melanin-concentrating hormone; MCR4, melanocortin receptor-4; NEFA, nonesterified fatty acid; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular hypothalamic nucleus; SON, supraoptic nucleus; UCP1, uncoupling protein-1

The effects of the cannabinoid-1 receptor (CB₁) 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 CB₁ 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 CB₁ 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 CB₁ 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 CB₁ antagonism from exerting beneficial effects on energy and glucose metabolism.

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				C. Doyon, P. Samson, J. Lalonde, and D. Richard Effects of the CRF1 receptor antagonist SSR125543 on energy balance and food deprivation-induced neuronal activation in obese Zucker rats J. Endocrinol., April 1, 2007; 193(1): 11 - 19. [Abstract] [Full Text] [PDF]