Kershaw Erin E, Schupp Michael, Guan Hong-Ping, Gardner Noah P, Lazar Mitchell A, Flier Jeffrey S
Div. of Endocrinology and Metabolism, Dept. of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA.
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1736-45. doi: 10.1152/ajpendo.00122.2007. Epub 2007 Sep 11.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic 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 PPARgamma 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 PPARgamma 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 PPARgamma-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARgamma, supporting the direct transcriptional regulation of ATGL by PPARgamma. 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, PPARgamma 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 PPARgamma's effects on lipid metabolism.
过氧化物酶体增殖物激活受体γ（PPARγ）调节参与脂肪生成和脂质代谢的脂肪细胞基因，并且是噻唑烷二酮（TZD）抗糖尿病药物的分子靶点。脂肪甘油三酯脂肪酶（ATGL）是一种最近被描述的甘油三酯特异性脂肪酶，在脂肪生成过程中被诱导，并且在成熟脂肪细胞中保持高表达。本研究评估PPARγ在体外和体内直接调节脂肪细胞中ATGL表达的能力。在完全分化的3T3-L1脂肪细胞中，TZD和非TZD的PPARγ激动剂以剂量和时间依赖性方式增加ATGL mRNA和蛋白质水平。罗格列酮介导的ATGL mRNA诱导迅速，并且不受蛋白质合成抑制剂环己酰亚胺的抑制，表明这种效应不需要中间的蛋白质合成。罗格列酮介导的ATGL mRNA和蛋白质诱导被PPARγ特异性拮抗剂GW-9662抑制，并且在PPARγ的siRNA介导的敲低后也显著降低，支持PPARγ对ATGL的直接转录调节。在体内，无论小鼠是否因高脂饮食或瘦素缺乏而肥胖，罗格列酮处理均可增加白色和棕色脂肪组织中的ATGL mRNA和蛋白质水平。因此，PPARγ在体外成熟脂肪细胞和体内脂肪组织中正向调节ATGL mRNA和蛋白质表达，提示ATGL在介导PPARγ对脂质代谢的作用中发挥作用。
