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Submitted on August 31, 2006
Accepted on January 24, 2007
-hydroxysteroid dehydrogenase type 1
Laval Hospital Research Center and Department of Anatomy & Physiology, Faculty of Medicine, Laval University, Québec, QC, Canada. Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Québec, QC, Canada; Department of External Scientific Affairs, Merck Research Laboratories, Rahway, NJ, USA
* To whom correspondence should be addressed. E-mail: yves.deshaies{at}phs.ulaval.ca.
The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11
-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacologic 11-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intra-abdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11-HSD1 inhibitor (Compound A, 3 mg/kg/day) for 3 weeks. 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 CPT1. In striking contrast, in the epididymal depot, 11-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased CPT1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacologic inhibition of 11-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenteric adipose depot, exerts divergent intra-abdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.
-HSD1 inhibitor •
glucocorticoid •
visceral adipose tissue •
blood lipids
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