PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo.
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.
Kershaw
Erin E
EE
Div. of Endocrinology and Metabolism, Dept. of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA. ekershaw@bidmc.harvard.edu
Schupp
Michael
M
Guan
Hong-Ping
HP
Gardner
Noah P
NP
Lazar
Mitchell A
MA
Flier
Jeffrey S
JS
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020738:Leptin / Q000235:genetics; D008049:Lipase; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D000217:Acyltransferases
D000813:Anilides; D002265:Carboxylic Ester Hydrolases; D003513:Cycloheximide; D004041:Dietary Fats; D005449:Fluorenes; D020738:Leptin; D008049:Lipase; D008565:Membrane Proteins; D047495:PPAR gamma; D015230:Prostaglandin D2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C457499:2-chloro-5-nitrobenzanilide; C496789:9-fluorenylmethoxycarbonyl; C436316:adiponutrin; C037112:9-deoxy-delta-9-prostaglandin D2; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases; C115174:netoglitazone