title: Major involvement of mTOR in the PPARγ-induced stimulation of adipose tissue lipid uptake and fat accretion.
abstract: Evidence points to a role of the mammalian target of rapamycin (mTOR) signaling pathway as a regulator of adiposity, yet its involvement as a mediator of the positive actions of peroxisome proliferator-activated receptor (PPAR)γ agonism on lipemia, fat accretion, lipid uptake, and its major determinant lipoprotein lipase (LPL) remains to be elucidated. Herein we evaluated the plasma lipid profile, triacylglycerol (TAG) secretion rates, and adipose tissue LPL-dependent lipid uptake, LPL expression/activity, and expression profile of other lipid metabolism genes in rats treated with the PPARγ agonist rosiglitazone (15 mg/kg/day) in combination or not with the mTOR inhibitor rapamycin (2 mg/kg/day) for 15 days. Rosiglitazone stimulated adipose tissue mTOR complex 1 and AMPK and induced TAG-derived lipid uptake (136%), LPL mRNA/activity (2- to 6-fold), and fat accretion in subcutaneous (but not visceral) white adipose tissue (WAT; 50%) and in brown adipose tissue (BAT; 266%). Chronic mTOR inhibition attenuated the upregulation of lipid uptake, LPL expression/activity, and fat accretion induced by PPARγ activation in both subcutaneous WAT and BAT, which resulted in hyperlipidemia. In contrast, rapamycin did not affect most of the other WAT lipogenic genes upregulated by rosiglitazone. Together these findings demonstrate that mTOR is a major regulator of adipose tissue LPL-mediated lipid uptake and a critical mediator of the hypolipidemic and lipogenic actions of PPARγ activation.
authors.affiliation: Department of Medicine, Faculty of Medicine, Quebec Heart & Lung Institute, Laval University, Quebec G1V 4G5, Canada.
authors.forename: Pierre-Gilles
authors.initials: PG
authors.lastname: Blanchard
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
authors.forename: Vanessa P
authors.initials: VP
authors.lastname: Houde
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Pierre
authors.forename: Sophie
authors.initials: S
authors.lastname: Brûlé
authors.forename: Véronique
authors.initials: V
authors.lastname: Turcotte
authors.forename: Marie
authors.initials: M
authors.lastname: Côté
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bellmann
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006868:Hydrolysis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D058570:TOR Serine-Threonine Kinases; D008071:Lipoprotein Lipase; D020123:Sirolimus