Major involvement of mTOR in the PPARγ-induced stimulation of adipose tissue lipid uptake and fat accretion

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. 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. Activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, a master regulator of adipogenesis and adipocyte lipid metabolism (1.Rosen E.D. MacDougald O.A. Adipocyte differentiation from the inside out.Nat. Rev. Mol. Cell Biol. 2006; 7: 885-896Crossref PubMed Scopus (1941) Google Scholar, 2.Festuccia W.T. Deshaies Y. Depot specificities of PPARγ ligand actions on lipid and glucose metabolism and their implication in PPARγ-mediated body fat redistribution.Clinical Lipidology. 2009; 4: 633-642Crossref Scopus (8) Google Scholar), is associated with marked fat accretion in subcutaneous white adipose (WAT) and brown adipose (BAT) tissues. We have shown in rodent models that such fat accretion is mainly attributable to the vastly enhanced uptake and storage of circulating lipids due to increased expression of genes involved in lipid uptake and esterification (2.Festuccia W.T. Deshaies Y. Depot specificities of PPARγ ligand actions on lipid and glucose metabolism and their implication in PPARγ-mediated body fat redistribution.Clinical Lipidology. 2009; 4: 633-642Crossref Scopus (8) Google Scholar–6.Festuccia W.T. Blanchard P.G. Turcotte V. Laplante M. Sariahmetoglu M. Brindley D.N. Deshaies Y. Depot-specific effects of the PPARγ agonist rosiglitazone on adipose tissue glucose uptake and metabolism.J. Lipid Res. 2009; 50: 1185-1194Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). This in turn is thought to be largely responsible for the marked postprandial hypolipidemic action of PPARγ activation in these models, with some contribution from reduced liver VLDL secretion (7.Laplante M. Festuccia W.T. Soucy G. Blanchard P.G. Renaud A. Berger J.P. Olivecrona G. Deshaies Y. Tissue-specific postprandial clearance is the major determinant of PPARγ-induced triglyceride lowering in the rat.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: R57-R66Crossref PubMed Scopus (35) Google Scholar). Therefore, when solicited, the PPARγ pathway brings about an integrated set of metabolic adaptations that leads to fat deposition in metabolically safe adipose compartments, a concomitant reduction in circulating lipids, and less exposure of nonadipose tissues to lipotoxicity. This process is thought to contribute to the powerful insulin-sensitizing action of PPARγ agonists, such as thiazolidinediones (8.Larsen T.M. Toubro S. Astrup A. PPARγ agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?.Int. J. Obes. Relat. Metab. Disord. 2003; 27: 147-161Crossref PubMed Scopus (246) Google Scholar). Although of definite importance, PPARγ is only one of many key modulators of adiposity. More specifically, robust evidence points to an important role of the mammalian target of rapamycin (mTOR) signaling pathway as a possible regulator of adipose tissue mass. mTOR is a conserved serine-threonine kinase that controls protein synthesis; cell size and proliferation according to the availability of amino acids; growth factors; nutrients; and cell energy status (9.Laplante M. Sabatini D.M. mTOR signaling at a glance.J. Cell Sci. 2009; 122: 3589-3594Crossref PubMed Scopus (1642) Google Scholar). mTOR is the catalytic core of two distinct multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), that have different downstream targets, biological functions, and sensitivity to inhibition by the bacterial macrolide rapamycin. Whereas mTORC1 activity is broadly inhibited by rapamycin, mTORC2 is negatively affected by this molecule after prolonged treatment and in certain cell types only (10.Sarbassov D.D. Ali S.M. Sengupta S. Sheen J.H. Hsu P.P. Bagley A.F. Markhard A.L. Sabatini D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.Mol. Cell. 2006; 22: 159-168Abstract Full Text Full Text PDF PubMed Scopus (2178) Google Scholar). With regard to adiposity, expansion of fat mass in obesity, for example, is associated with marked activation of mTOR in adipose tissue (11.Um S.H. Frigerio F. Watanabe M. Picard F. Joaquin M. Sticker M. Fumagalli S. Allegrini P.R. Kozma S.C. Auwerx J. et al.Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.Nature. 2004; 431: 200-205Crossref PubMed Scopus (1358) Google Scholar), whereas fat mass retraction due to caloric restriction and fasting is associated with adipose tissue mTOR inhibition. Accordingly, chronic pharmacological or genetic inhibition of the mTORC1 signaling pathway is associated with a reduction in adipose tissue mass due to both reduced adipocyte size and number (11.Um S.H. Frigerio F. Watanabe M. Picard F. Joaquin M. Sticker M. Fumagalli S. Allegrini P.R. Kozma S.C. Auwerx J. et al.Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.Nature. 2004; 431: 200-205Crossref PubMed Scopus (1358) Google Scholar–13.Polak P. Cybulski N. Feige J.N. Auwerx J. Ruegg M.A. Hall M.N. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration.Cell Metab. 2008; 8: 399-410Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar). Despite the direct association between mTOR activity and adiposity, little is known of the mechanisms by which mTOR modulates fat mass. Importantly, evidence suggests that mTOR may affect adiposity by modulating the activity of PPARγ. Pharmacological mTOR inhibition, for example, impairs in vitro preadipocyte differentiation into mature adipocytes through PPARγ inhibition (14.Kim J.E. Chen J. Regulation of peroxisome proliferator-activated activity by mammalian target of rapamycin and amino in 2004; PubMed Scopus Google Scholar), an by the of a PPARγ in rapamycin treatment adipose tissue expression of PPARγ target genes S. Festuccia W.T. Blanchard P.G. Deshaies Y. A. Chronic rapamycin treatment glucose and by and lipid deposition in adipose PubMed Scopus Google Scholar). evidence points to a possible between PPARγ and to such not yet in the in that PPARγ activation subcutaneous and brown fat accretion in and that mTOR as an important regulator of adiposity, we in the the that mTOR is a major mediator of the increased lipid uptake, fat accretion, and reduction in induced by PPARγ activation in this rats treated with the PPARγ agonist rosiglitazone in combination or not with the mTORC1 inhibitor rapamycin evaluated for plasma triacylglycerol (TAG) and uptake by adipose activity and expression of lipoprotein lipase the major determinant of and expression of other key genes involved in uptake and and treatment by the and of rats from in a at with a a rats by and into and rapamycin. or rapamycin (2 mg/kg/day) of rapamycin on its to the mTOR pathway in rats and a the of in Y. Y. J. PubMed Scopus Google Scholar, S. in 2003; PubMed Scopus Google Scholar). a rodent or with the PPARγ agonist rosiglitazone at a of 15 for 15 days. This of rosiglitazone in to be associated with subcutaneous fat accretion and in the plasma lipid profile M. Berger J.P. Deshaies Y. activation adipose effects on expression and lipoprotein lipase mechanisms for of postprandial and adipose 2003; PubMed Scopus Google Scholar). 15 of rats by for tissue and after a fasting or not by of by and by according to the in to and to as S. Festuccia W.T. Blanchard P.G. Deshaies Y. A. Chronic rapamycin treatment glucose and by and lipid deposition in adipose PubMed Scopus Google Scholar). for in with to the contribution to of of into the from the and liver a and of the an from the in an and rats through the with 1 a that S. of a to of triglyceride into the of the different Physiol. PubMed Scopus Google Scholar). and after the with a of and plasma and at for of of in the from of in plasma for plasma from body and as (7.Laplante M. Festuccia W.T. Soucy G. Blanchard P.G. Renaud A. Berger J.P. Olivecrona G. Deshaies Y. Tissue-specific postprandial clearance is the major determinant of PPARγ-induced triglyceride lowering in the rat.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: R57-R66Crossref PubMed Scopus (35) Google Scholar). of and of into adipose tissue lipids as M. in lipoprotein lipase activity by in Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. of in adipose tissue and by J. Physiol. Metab. 2004; PubMed Scopus (35) Google Scholar). tissue into and for with 1 of of and and for in a 1 of lipoprotein as P.P. and in with and type 2 a of Full Text Full Text PDF PubMed Scopus Google Scholar). and activity by in an and fasting into with a to that of in a at adipose tissue with 2 of and at with 1 of and lipids in tissue by direct of the tissue lipid activity of the responsible for the of circulating by of adipose for 1 at with of a of which and in as as as a of and or 2 by LPL from and in a LPL activity by activity in a of 1 from activity in a of M. LPL activity as 1 of at and as W.T. Laplante M. M. Y. Deshaies Y. PPARγ agonism adipose tissue expression of and the of to 2006; PubMed Scopus Google Scholar). In to we expression of key genes involved in uptake by LPL-mediated and esterification protein 1 protein known as kinase and and two PPARγ target genes and the glucose in as the between the expression of the target and the known as the expression of which not affected by rosiglitazone or rapamycin as by for as the of we evaluated treatment effects on the activation of signaling mTORC1 and 2 and AMPK by PPARγ and a known inhibitor of mTOR in rosiglitazone adipose tissue mTORC1 as by the increased of a downstream target protein in the mTORC1 signaling Rosiglitazone reduced the of that of the mTORC2 with activation of adipose tissue mTORC1 by a marked of as by the increased of and S. Festuccia W.T. Blanchard P.G. Deshaies Y. A. Chronic rapamycin treatment glucose and by and lipid deposition in adipose PubMed Scopus Google Scholar), rapamycin inhibited adipose tissue mTORC1 and 2 as through reduced and of rapamycin, on adipose tissue AMPK of rosiglitazone and rapamycin upregulation and attenuated the increased induced by rosiglitazone in adipose in rapamycin attenuated mTORC1 and 2 signaling and upregulation associated with rosiglitazone treatment in WAT and rosiglitazone inhibited mTORC2 in as by on the activity of this protein complex in subcutaneous and P.P. J. inhibits and to of Sci. 2008; PubMed Scopus Google Scholar), the action of rapamycin on tissue of treatment the evaluated in the liver S. Festuccia W.T. Blanchard P.G. Deshaies Y. A. Chronic rapamycin treatment glucose and by and lipid deposition in adipose PubMed Scopus Google Scholar), rapamycin treatment inhibited mTOR signaling in the liver and This associated with activation of AMPK as by an in In to adipose rosiglitazone treatment did not mTOR signaling in the the combination of both the activation of AMPK induced by rapamycin findings that some of the effects of PPARγ activation and mTOR inhibition to be to adipose tissue treated with rosiglitazone body and a to have and rats W.T. S. Laplante M. M. S. M.N. et proliferator-activated positive energy in the at is associated with reduced to adipose tissues and 2008; PubMed Scopus Google Scholar). on the other reduced body in and an due to a reduction in both and and adipose for body of rats treated with rapamycin rosiglitazone for 15 not a different from not a different from not a different from not a different from not a different from not a different from not a different from not a different from as of body of not a different from not a different from not a different from not a different from fat not a different from not a different from not a different from not a different from fat not a different from not a different from not a different from not a different from fat not a different from not a different from not a different from not a different from not a different from not a different from not a different from not a different from the body at the of not a different from as of body of in a the body at the of rapamycin growth and energy in fat to body to the of these rapamycin effects on the of the in adiposity. body of rats associated with an in adiposity which be mainly to an enhanced fat accretion in the subcutaneous WAT and M. Berger J.P. Deshaies Y. activation adipose effects on expression and lipoprotein lipase mechanisms for of postprandial and adipose 2003; PubMed Scopus Google Scholar, M. Festuccia W.T. Soucy G. Y. J. Berger J.P. Deshaies Y. of the of peroxisome proliferator-activated receptor action on adipose tissue 2006; PubMed Scopus Google Scholar, W.T. Blanchard P.G. Turcotte V. Laplante M. Sariahmetoglu M. Brindley D.N. Deshaies Y. agonist rosiglitazone brown adipose tissue from glucose glucose J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: PubMed Scopus Google Scholar, W.T. Blanchard P.G. Turcotte V. Laplante M. Sariahmetoglu M. Brindley D.N. Deshaies Y. Depot-specific effects of the PPARγ agonist rosiglitazone on adipose tissue glucose uptake and metabolism.J. Lipid Res. 2009; 50: 1185-1194Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar), of rosiglitazone on WAT mass on the other reduced adiposity and mass and attenuated the upregulation induced by rosiglitazone in adiposity and of WAT and WAT mass to in rats treated with both upregulation of subcutaneous fat accretion by rosiglitazone treatment associated with an in plasma which attenuated by rapamycin in the actions of rosiglitazone and rapamycin on plasma lipids the In fasting in plasma and between the the of of after the rosiglitazone reduced plasma of and on the other increased plasma and and the action of rosiglitazone In to rapamycin did not affect the reduction in plasma induced by rosiglitazone the mechanisms by which rapamycin and rosiglitazone lipemia, we both of the in of liver and secretion and adipose tissue clearance of a lipid rosiglitazone and rapamycin only in of secretion and adipose tissue clearance only in the rosiglitazone and rapamycin induced a marked in the of secretion and combination of both in these effects in the not In of (7.Laplante M. Festuccia W.T. Soucy G. Blanchard P.G. Renaud A. Berger J.P. Olivecrona G. Deshaies Y. Tissue-specific postprandial clearance is the major determinant of PPARγ-induced triglyceride lowering in the rat.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: R57-R66Crossref PubMed Scopus (35) Google Scholar), rosiglitazone increased the of some adipose tissues to and TAG-derived as by the in the of from a in WAT and BAT, not in WAT on the other reduced into lipids in WAT and their upregulation by rosiglitazone in WAT and robust of adipose tissue lipid clearance by rosiglitazone associated with a marked in LPL activity and in and brown fat and to a in fat on the other reduced LPL activity and in WAT and LPL in and their upregulation by rosiglitazone. of the of LPL-dependent lipid uptake in the of adiposity by rosiglitazone and rapamycin, between of in we between LPL and lipid uptake, that LPL-mediated lipid is a major in the of adiposity rosiglitazone rapamycin robust between these in BAT, not in WAT not the of rosiglitazone action subcutaneous white and brown fat between adipose tissue LPL and TAG-derived lipid uptake in rats treated with rapamycin or rosiglitazone for 15 days. an PPARγ genes other LPL that involved in lipid and and rapamycin to the reduction in plasma to we mTOR a role by in fat the of of PPARγ target shown in rosiglitazone increased of its target genes involved in the uptake and and storage into of in the uptake of glucose and in the of upregulation of and expression by rapamycin, whereas of the other lipogenic genes stimulated the the treatment to the expression of its target genes in WAT and in the only stimulated this the mechanisms by which mTOR with PPARγ-mediated we PPARγ activity in the fat in rapamycin treatment the of PPARγ to its In the by a combination of rosiglitazone and rapamycin we to of the complex between the PPARγ and mTOR in the of adiposity, adipose tissue lipid uptake, and findings demonstrate that mTOR is an important regulator of adiposity, TAG-derived lipid uptake and LPL and as as its role as a critical mediator of the positive actions of rosiglitazone these More specifically, mTORC1 is in adipose tissue by PPARγ and as a key mediator of the positive actions of rosiglitazone LPL lipid and subcutaneous and brown fat results mTOR as a of PPARγ lipid and adiposity in In with the of a possible implication of mTOR in the positive actions of PPARγ activation on adiposity, the the as yet of rosiglitazone to mTORC1 in adipose as by the increased of in adipose and that of in by which rosiglitazone mTORC1 at the the reduction in and of in that rosiglitazone mTORC1 by a that not an in insulin one of the major of PPARγ activation in rosiglitazone mTORC1 a kinase that inhibits mTORC1 activity by raptor D.M. A. AMPK of raptor a metabolic Cell. 2008; Full Text Full Text PDF PubMed Scopus Google and Y. J. is and inhibited by and mTOR Cell Biol. 4: PubMed Scopus Google Scholar). results in with a activation of mTORC1 and AMPK in the rosiglitazone treatment W.T. Laplante M. S. A. J. et is associated with enhanced of protein and mTOR Mol. Cell. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). AMPK activity a of mTORC1 by rosiglitazone by an which S. Festuccia W.T. Blanchard P.G. Deshaies Y. A. Chronic rapamycin treatment glucose and by and lipid deposition in adipose PubMed Scopus Google Scholar, W.T. S. Laplante M. M. S. M.N. et proliferator-activated positive energy in the at is associated with reduced to adipose tissues and 2008; PubMed Scopus Google Scholar), body enhanced by rosiglitazone and reduced by rapamycin or in combination with rosiglitazone. findings that mTOR inhibition the positive actions of PPARγ activation on energy this the mechanisms the marked reduction in body by rapamycin reduced the major in in the suggests an in energy as its rapamycin affected as from energy and core not that is not involved in the enhanced energy rapamycin is to the mechanisms the in energy by pharmacological mTOR inhibition. Although energy and energy many affect energy fat accretion in adipose We in the a direct between adipose tissue mTORC1 activation status and adiposity, which body to into the of the in energy and growth induced by rapamycin. tissue mTORC1 activation by rosiglitazone associated with an in adiposity, which mainly due to subcutaneous and brown fat accretion, whereas pharmacological mTOR inhibition with rapamycin associated with reduced adiposity. Importantly, mTOR inhibition attenuated the in adiposity and subcutaneous and brown fat induced by mTOR as a major of adiposity and as a critical mediator of the fat accretion induced by pharmacological PPARγ activation. Despite the reduction in both adipose tissue mTORC1 and 2 the of adiposity rapamycin treatment to be due to mTORC1 mTORC2 inhibition. of adipose tissue mTORC2 activity by results in increased and fat A. M.A. of in mice impairs fat cell and glucose and lipid PubMed Scopus Google Scholar, N. P. Auwerx J. Ruegg M.A. Hall M.N. mTOR complex 2 in adipose tissue negatively controls Sci. 2009; PubMed Scopus Google Scholar), which is the of the with rapamycin the other as with rapamycin adipose inhibition of mTORC1 by raptor P. Cybulski N. Feige J.N. Auwerx J. Ruegg M.A. Hall M.N. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration.Cell Metab. 2008; 8: 399-410Abstract Full Text Full Text PDF PubMed Scopus (386) Google and body knockout of the mTORC1 downstream target (11.Um S.H. Frigerio F. Watanabe M. Picard F. Joaquin M. Sticker M. Fumagalli S. Allegrini P.R. Kozma S.C. Auwerx J. et al.Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.Nature. 2004; 431: 200-205Crossref PubMed Scopus (1358) Google both in reduced adiposity and against diet-induced In to adiposity, the adipose tissue mTOR activation status to plasma mTOR inhibition by rapamycin and activation by rosiglitazone associated with and an involvement of mTOR in the of plasma PPARγ rapamycin treatment the action of rosiglitazone. In the we the as yet the associated with mTOR inhibition. is one of the major effects and rapamycin and one of the most for treatment G. S. of on plasma lipids, lipoprotein and metabolism in Lipid Res. Full Text Full Text PDF PubMed Google Scholar, G. Y. J. in treated with PubMed Scopus Google Scholar, S. M. P. A. M. in a PubMed Scopus Google Scholar, Hsu A. an mTOR inhibitor for treatment of with cell J. 2008; PubMed Scopus Google Scholar, M. M. Y. M. J. N. et inhibition by rapamycin to and the metabolic in type 2 2008; PubMed Scopus Google an mTOR triglyceride metabolism in 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). the between and liver lipoprotein secretion and LPL-mediated clearance in adipose responsible for a of body lipid clearance in the postprandial findings that pharmacological mTOR inhibition with rapamycin, in the of vastly reduced resulted in that an in the of adipose tissue to and circulating lipids is a major determinant of the In with this rapamycin treatment reduced the of adipose tissue to from a lipid in the upregulation of this process induced by which the major role of adipose lipid uptake in in the findings that the in adipose tissue lipid induced by rapamycin rosiglitazone at in for the in adiposity in the In with this we a between subcutaneous fat accretion and lipid Although the in energy by rapamycin may a in the involvement of PPARγ and mTOR in the of lipid be that PPARγ whereas rapamycin a reduction in not of mechanisms to energy a direct involvement of PPARγ and mTOR in the of plasma and adipose tissue lipid tissue clearance of circulating lipids is mainly by an that circulating and for tissue the mTORC1 actions adipose tissue lipid activation of mTORC1 by rosiglitazone associated with a in LPL and activity in and brown whereas pharmacological mTOR inhibition not only reduced LPL expression and activity in rats attenuated their activation by rosiglitazone. In we a between subcutaneous fat accretion, lipid uptake, and LPL that mTORC1 the storage of energy by modulating the of adipose tissue to and circulating lipids at of of other PPARγ genes to the upregulation in by rosiglitazone on mTOR is a that the of into the for esterification and Y. M.A. metabolic in adipocytes by 8: PubMed Scopus Google Scholar). LPL and have in their a and their is increased by PPARγ Y. M.A. metabolic in adipocytes by 8: PubMed Scopus Google Scholar, J. M. S. Auwerx J. and PPARγ direct a distinct a in the lipoprotein lipase J. PubMed Scopus Google Scholar), the of the upregulation in their by rapamycin suggests that mTOR signaling is for PPARγ activity a of More the sensitivity of PPARγ activity to mTOR to be as rapamycin the of rosiglitazone to lipogenic genes in fat and BAT, in to the the of the glucose the and and the key not negatively affected by the of of mTOR inhibition on the of key genes in the may the PPARγ agonist remains to circulating to Although the mechanisms this mTOR at the the of in PPARγ by rapamycin suggests that or of PPARγ its in receptor findings not only in receptor as a possible mediator of rapamycin effects that some genes to of PPARγ Although the findings that mTOR signaling is for PPARγ a of positive between the PPARγ and in which PPARγ activation adipose tissue mTORC1 activity in PPARγ action some be in of such as obesity, mTOR activation adipose tissue PPARγ activity genes that the and to the as in a of to between PPARγ and in which in plasma associated with PPARγ activation in and secretion Laplante M. A. S.M. G. et in metabolic profile through expansion of adipose PubMed Scopus Google Scholar). mice to and subcutaneous fat accretion to is rosiglitazone treatment Laplante M. A. S.M. G. et in metabolic profile through expansion of adipose PubMed Scopus Google Scholar). its actions in adipose tissue in by AMPK N. and in insulin and the metabolic 2006; PubMed Scopus Google Scholar, and Rev. PubMed Scopus Google Scholar), which is a known inhibitor of mTORC1 findings that rosiglitazone treatment in plasma adipose tissue AMPK in rats or and subcutaneous fat accretion that mTOR is important in the of these by the mechanisms mTOR of the between and PPARγ In we have shown in the that mTOR is in the of plasma lipid and adiposity and is a key mediator of in upregulation of adipose tissue LPL lipid and fat accretion induced by rosiglitazone. PPARγ agonists little to and rapamycin the of reduced postprandial remains to be the of the mechanisms by which mTOR modulates PPARγ be of in the of pharmacological to PPARγ activity and adiposity. for with brown adipose tissue mammalian target of rapamycin peroxisome proliferator-activated receptor triacylglycerol white adipose tissue

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