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Chaire de recherche Merck Frosst/IRSC sur l’obésité and Centre de recherche de l’Hôpital Laval, Hôpital Laval, 2725 chemin Sainte-Foy, Québec, Canada G1V 4G5

(Requests for offprints should be addressed to D Richard; Email: denis.richard{at}crhl.ulaval.ca)

(The present address of C Doyon is the Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada K1H 8M5)

The corticotropin-releasing factor (CRF) system is involved in numerous physiological and behavioral actions, including the regulation of energy balance. We examined the effects of the CRF₁ receptor antagonist, SSR125543, on energy balance and food deprivation-induced neuronal activation in obese rats. Lean (Fa/?) and obese (fa/fa) Zucker rats were treated orally with SSR125543 at a daily dose of 30 mg/kg for 21 days. Rats were killed either fed ad libitum or food deprived for 6 h in order to induce a mild stress response in obese rats. SSR125543 reduced plasma corticosterone levels in lean rats, prevented corticosterone response to fasting in obese rats, and increased CRF mRNA levels in the paraventricular hypothalamic nucleus (PVN) of both lean and obese rats, further confirming that the antagonist partially blocked CRF₁ receptors. SSR125543 increased protein gain in obese rats. Whole carcass analyses showed reduced energy and fat gains in lean rats. Consistent with reduced fat gain, circulating triglyceride and leptin levels were reduced in SSR125543-treated lean rats. In obese rats, circulating glucose levels and the homeostasis model assessment of insulin resistance index of insulin resistance were reduced by SSR125543 treatment. CRF₁ receptor blockade increased uncoupling protein-1 mRNA levels in interscapular brown adipose tissue of obese rats. The antagonist partly blocked the fasting-induced changes in c-fos mRNA levels in the PVN and arcuate nucleus of obese rats. Overall, these results suggest that although SSR125543 had relatively mild effects on energy balance, CRF₁ receptor blockade attenuated several metabolic effects of short-term fasting and improved plasma variables related to the metabolic syndrome and diabetes.