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Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1

Laval Hospital Research Center and Department of Anatomy and Physiology (M.B., M.L., W.F., Y.G., S.P., J.L., Y.D.) and Division of Kinesiology, Department of Social and Preventive Medicine (D.R.J.), Faculty of Medicine, Laval University, Quebec, Canada G1V 4G5; and Department of External Scientific Affairs (R.T.), Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Dr. Yves Deshaies, Laval Hospital Research Center, Laval Hospital, 2725 Chemin Sainte-Foy Québec, Quebec, Canada G1V 4G5. E-mail: yves.deshaies{at}phs.ulaval.ca.

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11ß-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11ß-HSD1 inhibitor (compound A, 3 mg/kg·d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (–18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25–50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11ß-HSD1 inhibition increased (1.5–5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11ß-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.

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