Nature Medicine8, 1122 - 1128 (2002)
Published online: 23 September 2002; | doi:10.1038/nm780
A futile metabolic cycle activated in adipocytes by antidiabetic agents
Hong-Ping Guan1, Yong Li1, Mette Valentin Jensen2, Christopher B. Newgard2, Claire M. Steppan1
& Mitchell A. Lazar1
1
Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine, Genetics, and Pharmacology, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
2
Sarah Stedman Center for Nutritional Studies and Duke Program in Diabetes Research, Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.
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, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.
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