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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/E211    most recent 91014.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yang, G. Articles by Samad, F. PubMed PubMed Citation Articles by Yang, G. Articles by Samad, F.

Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome

¹Torrey Pines Institute for Molecular Studies, San Diego, California; ²Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina; ³The Scripps Research Institute, La Jolla, California

Submitted 31 December 2008 ; accepted in final form 2 May 2009

Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor- (TNF-) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.

sphingolipids; insulin resistance; leptin resistance; insulin resistance; suppressor of cytokine signaling-3; tumor necrosis factor-; plasminogen activator inhibitor-1; monocyte chemoattactant protein-1