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1Veterans Affairs Palo Alto Health Care System, Palo Alto 94304; 2Department of Medicine, Stanford University, Stanford, California 94305; 3Department of Metabolic Diseases, University of Tokyo, Tokyo 113-8655; and 4Department of Internal Medicine, Jichi Medical School, Tochigi 329-0498, Japan
Submitted 11 June 2003 ; accepted in final form 21 August 2003
To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL–/–) and wild-type mice were fed normal chow or high-fat diets. HSL–/– mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL–/– mice. Serum insulin levels in the fed state and tumor necrosis factor-
mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL–/– mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-
, CAAT/enhancer-binding protein-) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL–/– mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL–/– mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.
adipocyte; differentiation; insulin; leptin; fatty liver
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