Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1.
The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-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 11beta-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, 11beta-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 11beta-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.
Berthiaume
Magalie
M
Laval Hospital Research Center, Department of Anatomy and Physiology, Laval University, Quebec, Canada G1V 4G5.
Laplante
Mathieu
M
Festuccia
William
W
Gélinas
Yves
Y
Poulin
Sébastien
S
Lalonde
Josée
J
Joanisse
Denis R
DR
Thieringer
Rolf
R
Deshaies
Yves
Y
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050153:Abdominal Fat / Q000201:enzymology*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D019422:Dietary Sucrose / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D008066:Lipolysis / Q000502:physiology; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D010741:Phospholipases A / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
D019422:Dietary Sucrose; D004791:Enzyme Inhibitors; C491899:Fas protein, mouse; D012333:RNA, Messenger; D019014:fas Receptor; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D013230:Stearoyl-CoA Desaturase; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D010741:Phospholipases A; D010729:Phosphoenolpyruvate Carboxykinase (GTP)