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REGULATES ADIPOSE TRIGLYCERIDE LIPASE IN ADIPOCYTES IN VITRO AND IN VIVO
1 Department of Medicine / Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
2 Department of Medicine, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
3 Philadelphia, Pennsylvania, United States; Department of Medicine, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
4 Department of Medicine / Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States; Boston, Massachusetts, United States
5 Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia,, Pennsylvania, United States
6 Endocrine / Medicine, Beth Israel Deaconess Med Ctr, 330 Brookline Ave., Boston, Massachusetts, 02215, United States; Department of Medicine / Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: ekershaw{at}bidmc.harvard.edu.
Peroxisome proliferator-activated receptor gamma (PPAR
) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) anti-diabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPAR to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPAR agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPAR-specific antagonist GW9662 and is also significantly reduced following siRNA-mediated knockdown of PPAR, supporting the direct transcriptional regulation of ATGL by PPAR. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin-deficiency. Thus, PPAR positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPAR's effects on lipid metabolism.
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