Depot-specific effects of the PPARγ agonist rosiglitazone on adipose tissue glucose uptake and metabolism

We investigated mechanisms whereby peroxisome proliferator-activated receptor γ (PPARγ) agonism redistributes lipid from visceral (VF) toward subcutaneous fat (SF) by studying the impact of PPARγ activation on VF and SF glucose uptake and metabolism, lipogenesis, and enzymes involved in triacylglycerol (TAG) synthesis. VF (retroperitoneal) and SF (inguinal) of rats treated or not for 7 days with rosiglitazone (15 mg/kg/day) were evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (or lipin-1), and diacylglycerol acyltransferase. Rosiglitazone increased SF glucose uptake, GLUT4 mRNA, and insulin-stimulated glucose oxidation, conversion to lactate, glycogen, and the glycerol and fatty acid components of TAG. In VF, only glucose incorporation into TAG-glycerol was stimulated by rosiglitazone and less so than in SF (1.5- vs. 3-fold). mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF and again less so in VF. Rosiglitazone activated TAG-glycerol synthesis in vivo (2.8- vs. 1.9-fold) and lipin activity (4.6- vs. 1.5-fold) more strongly in SF than VF, whereas GPAT activity was increased similarly in both depots. The preferential increase in glucose uptake and intracellular metabolism in SF contributes to the PPARγ-mediated redistribution of TAG from VF to SF, which in turn favors global insulin sensitization. We investigated mechanisms whereby peroxisome proliferator-activated receptor γ (PPARγ) agonism redistributes lipid from visceral (VF) toward subcutaneous fat (SF) by studying the impact of PPARγ activation on VF and SF glucose uptake and metabolism, lipogenesis, and enzymes involved in triacylglycerol (TAG) synthesis. VF (retroperitoneal) and SF (inguinal) of rats treated or not for 7 days with rosiglitazone (15 mg/kg/day) were evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (or lipin-1), and diacylglycerol acyltransferase. Rosiglitazone increased SF glucose uptake, GLUT4 mRNA, and insulin-stimulated glucose oxidation, conversion to lactate, glycogen, and the glycerol and fatty acid components of TAG. In VF, only glucose incorporation into TAG-glycerol was stimulated by rosiglitazone and less so than in SF (1.5- vs. 3-fold). mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF and again less so in VF. Rosiglitazone activated TAG-glycerol synthesis in vivo (2.8- vs. 1.9-fold) and lipin activity (4.6- vs. 1.5-fold) more strongly in SF than VF, whereas GPAT activity was increased similarly in both depots. The preferential increase in glucose uptake and intracellular metabolism in SF contributes to the PPARγ-mediated redistribution of TAG from VF to SF, which in turn favors global insulin sensitization. White adipose tissue (WAT) plays an important role in whole-body homeostasis by acting both as an energy reservoir and as an endocrine gland secreting several adipokines that impact major metabolic tissues, such as the liver, muscle, and brain. The importance of WAT in the maintenance of a healthy whole-body homeostasis is highlighted by the direct relationship of disturbances in WAT function (obesity and lipodystrophy) with the development of several morbidities, such as Type 2 diabetes, cancer, and atherosclerosis. Peroxisome proliferator-activated receptorγ (PPARγ), a nuclear receptor mainly expressed in WAT, plays a key role in regulating adipose metabolic and endocrine functions. PPARγ is a master regulator of adipocyte differentiation, and its activation in vivo results in adipose tissue remodeling associated with lipid redistribution from visceral fat (VF) to subcutaneous fat (SF) (1Mori Y. Murakawa Y. Okada K. Horikoshi H. Yokoyama J. Tajima N. Ikeda Y. Effect of troglitazone on body fat distribution in type 2 diabetic patients.Diabetes Care. 1999; 22: 908-912Crossref PubMed Scopus (242) Google Scholar, 2Miyazaki Y. Mahankali A. Matsuda M. Mahankali S. Hardies J. Cusi K. Mandarino L.J. DeFronzo R.A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.J. Clin. Endocrinol. Metab. 2002; 87: 2784-2791Crossref PubMed Scopus (615) Google Scholar–3Smith S.R. De Jonge L. Volaufova J. Li Y. Xie H. Bray G.A. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial.Metabolism. 2005; 54: 24-32Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). More specifically, PPARγ activation in both humans and rodents is associated with an enhanced ability of SF to take up and store fatty acids, especially those derived from lipoprotein-bound triacylglycerol (TAG) through lipoprotein lipase (4Laplante M. Sell H. MacNaul K.L. Richard D. Berger J.P. Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003; 52: 291-299Crossref PubMed Scopus (134) Google Scholar). Directing fat away from VF to SF depots may constitute one mechanism whereby PPARγ agonism prevents the deleterious effects of VF accumulation on the development of the metabolic syndrome and the progression to cardiovascular disease. Glucose is the major substrate metabolized in WAT. It is used not only for the synthesis of glycerol 3-phosphate, the carbon backbone of TAG, and fatty acids by de novo lipogenesis, but it is also used to generate energy that supports fatty acid esterification and TAG synthesis and other adipocyte functions. Most of the glucose (∼50%) taken up by the adipocytes is normally used to synthesize the glycerol and fatty acid components of TAG, with the remainder being directed toward oxidation (∼30%) and the synthesis of lactate and glycogen (5DiGirolamo M. Newby F.D. Lovejoy J. Lactate production in adipose tissue: a regulated function with extra-adipose implications.FASEB J. 1992; 6: 2405-2412Crossref PubMed Scopus (204) Google Scholar). Although PPARγ ligands, due to their positive effects on whole body glucose homeostasis, are widely used in the treatment of insulin resistance, little is known about their effects on WAT glucose metabolism. Deletion of one PPARγ allele is associated with an impairment of WAT expression of several genes implicated in glucose uptake, glycolysis, glycogen synthesis, and the pentose pathway, suggesting a key involvement of PPARγ in controlling WAT glucose metabolism (6Anghel S.I. Bedu E. Vivier C.D. Descombes P. Desvergne B. Wahli W. Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma.J. Biol. Chem. 2007; 282: 29946-29957Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Whether the above changes in WAT gene expression translate into alterations of the corresponding metabolic processes in vivo and whether such changes are depot specific, as is the case for fat accretion, remains to be investigated. WAT provides an important contribution to whole-body glucose homeostasis (5DiGirolamo M. Newby F.D. Lovejoy J. Lactate production in adipose tissue: a regulated function with extra-adipose implications.FASEB J. 1992; 6: 2405-2412Crossref PubMed Scopus (204) Google Scholar), and changes in adipocyte intracellular glucose metabolism could be part of the fat redistribution induced by PPARγ agonism. This study assesses the effects of PPARγ activation in vivo on glucose metabolism in retroperitoneal and inguinal depots, which are representative of VF and SF, respectively. Rats treated with the thiazolidinedione, rosiglitazone, were evaluated in vivo for glucose uptake and lipogenesis, in vitro for glucose oxidation, and for its conversion to lactate, TAG, and glycogen. We also assessed the activities of key enzymes of TAG synthesis along with an extensive comparative analysis of the gene expression profile of VF and SF to investigate the mechanisms of rosiglitazone action. Experimental procedures were performed in accordance with the Canadian Guide for the Care and Use of Laboratory Animals and received prior approval of the Laval University animal care committee. Male Sprague-Dawley rats (Charles River, St. Constant, QC, Canada) were matched by and into and that received a (Charles energy and or with the PPARγ rosiglitazone a of for 7 Rats were with a was to glucose adipose insulin and lipemia of composition (4Laplante M. Sell H. MacNaul K.L. Richard D. Berger J.P. Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003; 52: 291-299Crossref PubMed Scopus (134) Google Scholar, M. Y. J. Berger J.P. Deshaies Y. of the depot of peroxisome proliferator-activated receptor on adipose tissue PubMed Scopus Google Scholar). The of rosiglitazone was on that its to fat from visceral to subcutaneous depots a of of treatment was to investigate the effects of rosiglitazone involved in lipid rosiglitazone was with the and the (15 was by the of to the and body of rats other The of glucose uptake by adipose depots was in vivo as L. M. M. The for the of glucose and in the and PubMed Scopus Google Scholar, P. A. L. J. to glucose in vivo in and adipose tissue of the J. PubMed Scopus Google Scholar). of a and were through a in the and of was and for and glucose were days the glucose uptake rats were by of and were used for the of of glucose uptake were as P. A. L. J. to glucose in vivo in and adipose tissue of the J. PubMed Scopus Google Scholar). glucose levels not the in a of the of WAT glycogen was performed as S. of glycogen in tissue PubMed Scopus Google Scholar). rats were with in rats were by were and the of was VF and SF (inguinal) were and for of incorporation into TAG. were with as J. M. for the and of from animal Biol. Chem. Full Text PDF PubMed Google and for the of incorporation into fatty acid of TAG S.R. Glucose contribution to in vivo synthesis of and fatty acids in rats to a Full Text PDF PubMed Scopus Google Scholar). of into TAG-glycerol was by the incorporation into and fatty of tissue fatty acid and glycerol synthesis were that glycerol and fatty acid into TAG and of acid synthesis in adipose tissue in PubMed Scopus Google Scholar, in with to lipogenesis and lipid and Biol. Chem. Full Text PDF PubMed Google Scholar). Glucose conversion to its in vitro was as M. of glucose conversion to its Biol. Google Scholar). were used than adipocytes to metabolic associated with and to the in vivo as as of the take into the that other than adipocytes may to treatment fat of SF and VF were in of and with fatty were with a with and and for in the or of insulin The insulin was to to that in vivo in the the of the were with and was with a and into a of in the to were and to lipid or glycogen as and were for lactate was used for glucose uptake the being the of glucose by were for of of as P. A. L. J. to glucose in vivo in and adipose tissue of the J. PubMed Scopus Google Scholar). are expressed as to for The was the Canada) the activity was in of adipose tissue in a and activity was by the of and The of and of Biol. Chem. Full Text PDF PubMed Google Scholar), on the incorporation of into as S.R. of activity in adipose J. 2003; PubMed Scopus Google Scholar). in the was by the acid of PubMed Scopus Google Scholar). activity was by of adipose tissue for with of a substrate of which Canada) and in as as fatty as a of and or 2 by was from and was in a activity was by activity in a of from activity in a of M. activity was expressed as fatty acid of The activity of is expressed adipose depot to the contribution of depots to TAG acyltransferase activity was as S. R.A. the metabolic of fatty acids in J. Endocrinol. Metab. 2005; PubMed Scopus Google Scholar, synthesis in fat that the and acyltransferase activities are of a Biol. Chem. Full Text PDF PubMed Google with Adipose were in and and for The was and for were in and evaluated for GPAT activity a on with or 2 The was of fatty acid and of were with of and of of and of acid were were and the was The was with and acyltransferase activity was as synthesis in fat on the diacylglycerol acyltransferase activity Biol. Chem. Full Text PDF PubMed Google with Adipose were in and for The was and for were in and evaluated for The was of and of in were with of of and of were and were The was and with and It that of the TAG in acid synthesis in fat on the diacylglycerol acyltransferase activity Biol. Chem. Full Text PDF PubMed Google Scholar). Adipose were in 2 phosphatidate phosphatase-1 and The were for and were the was to the to and increase the The were performed as J. M. J. K. as phosphatidate with tissue expression Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, B. M. J. M. K. and increase expression, and insulin Full Text Full Text PDF PubMed Scopus Google Scholar). The were in a of 2 fatty acid and acid with that was in and were for with of as and was J. M. J. K. as phosphatidate with tissue expression Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, B. M. J. M. K. and increase expression, and insulin Full Text Full Text PDF PubMed Scopus Google Scholar). activities were from to the of the were performed in the of to and to for activity in of were in and were with and with by synthesis in fat that the and acyltransferase activities are of a Biol. Chem. Full Text PDF PubMed Google Scholar). were the VF and SF and by were performed as S. M. M. S. proliferator-activated positive energy in the is associated with to adipose and PubMed Scopus Google Scholar). used for the are in are expressed as the the expression of the gene and the gene the expression of which is not by rosiglitazone glucose were with the glucose and insulin levels were by St. with insulin as TAG and levels were by QC, and are expressed as effects of rosiglitazone treatment were by was taken as the of body and body were increased and 7 days of rosiglitazone treatment The body of rats was associated with an increase in and SF whereas and VF were not Rosiglitazone increased levels of those of insulin and TAG but not glucose its metabolic and and in body body as body are of as body in a are of Glucose uptake in VF and mRNA levels of and were not by rosiglitazone In in SF, rosiglitazone increased glucose uptake both in vivo and in vitro in the of insulin levels and an that was associated with a increase in SF but not mRNA levels in the case of in vitro glucose uptake, treatment with rosiglitazone not VF or SF intracellular glucose metabolism in vitro for representative in adipose from of insulin not of the of intracellular glucose metabolism investigated for representative The results on the depot of of rosiglitazone on glucose metabolism evaluated in the of insulin levels in to uptake, insulin-stimulated glucose oxidation and conversion to lactate were not by rosiglitazone in VF. This was a increase in tissue mRNA levels of and lactate and of the and which are involved in and Krebs cycle, respectively. of rosiglitazone was in VF glycogen its synthesis from glucose and mRNA levels of and which as a and glucose for glycogen synthesis, a increase in glycogen 2 mRNA In SF, rosiglitazone increased of insulin-stimulated glucose oxidation conversion to lactate and mRNA levels of lactate and In SF, rosiglitazone also enhanced insulin-stimulated incorporation of glucose into glycogen which was associated with a increase in tissue glycogen and mRNA levels of and major depot-specific in glucose in to rosiglitazone, investigated whether such to lipid metabolism. Rosiglitazone increased insulin-stimulated glucose incorporation into VF TAG through enhanced synthesis of the glycerol of TAG from glucose This was associated with a increase in VF mRNA levels of major enzymes involved in synthesis of glycerol 3-phosphate, fatty acids, and TAG, glucose glycerol and also known as Rosiglitazone increased insulin-stimulated glucose incorporation into TAG also in in with VF, from increased synthesis of both the glycerol and fatty acid of TAG from glucose and Rosiglitazone increased mRNA levels of glycerol and to a in SF with VF. rosiglitazone glucose incorporation into TAG in investigated adipose tissue lipogenesis in vivo by the incorporation of from into both the glycerol and fatty acid components of TAG. This the not only of fatty acid synthesis from carbon those from but also glycerol synthesis from glucose by to the of and not that from Rosiglitazone markedly increased the synthesis of the glycerol of TAG in SF in vivo but less so in VF (2.8- and In the not of de novo fatty acid synthesis in of the depots. synthesis of the fatty acid and glycerol components of TAG was not by with TAG-glycerol synthesis, rosiglitazone markedly increased activity in both SF and VF lipase which provides fatty acids from was also stimulated by rosiglitazone in SF but less so in VF the depot-specific mechanisms by which rosiglitazone TAG synthesis in adipose tissue in the activities of key enzymes involved in in were GPAT and Rosiglitazone increased GPAT activity in VF and SF as a of an increase in both and activities This was associated with a increase in VF and SF mRNA levels of GPAT and but not Rosiglitazone increased SF and VF activity and changes were by in lipin The in activity (4.6- vs. and to a lipin were in SF with VF, and were associated with a more increase in mRNA levels of lipin and lipin in SF with VF vs. rosiglitazone treatment was associated with a increase in VF and SF activity and mRNA levels of its In SF, rosiglitazone increased mRNA levels and GPAT activities and mRNA of the GPAT and in VF and SF of rats treated or not with rosiglitazone for 7 the of mRNA levels of the lipin and and in VF and SF of rats treated or not with rosiglitazone for 7 the of are for and rats activity and mRNA levels of the and 2 in VF and SF of rats treated or not with rosiglitazone for 7 the of the mechanisms involved in fat redistribution and insulin induced by PPARγ activation in study investigated the impact and mechanisms of of rosiglitazone on VF and SF glucose metabolism and In SF, rosiglitazone markedly increased glucose uptake and insulin-stimulated glucose oxidation, conversion to lactate, and incorporation into glycogen and into both the glycerol and fatty acid components of TAG. The in vitro effects only in the of insulin a to in vivo that was to glucose metabolism in which that rosiglitazone the of SF glucose metabolism to the of In VF, only glucose incorporation into the glycerol of TAG was stimulated by rosiglitazone, and it was so to a than in The mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF, but less so in VF. Rosiglitazone also induced a more increase in the in vivo synthesis of the glycerol of TAG, and and lipin activities in SF with VF, whereas GPAT activity was similarly increased in both depots. depot-specific increase in SF mRNA levels was also induced by rosiglitazone, activity was to levels in both SF and VF. results toward an involvement of SF glucose metabolism in the fat redistribution and glucose induced by PPARγ agonism in This study that the positive of rosiglitazone on insulin sensitivity and lipemia increased body and subcutaneous In the rosiglitazone only to VF to VF in the (4Laplante M. Sell H. MacNaul K.L. Richard D. Berger J.P. Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003; 52: 291-299Crossref PubMed Scopus (134) Google Scholar, M. Y. J. Berger J.P. Deshaies Y. of the depot of peroxisome proliferator-activated receptor on adipose tissue PubMed Scopus Google Scholar). redistribution from VF to SF, a of PPARγ is to a role in the of PPARγ in humans (1Mori Y. Murakawa Y. Okada K. Horikoshi H. Yokoyama J. Tajima N. Ikeda Y. Effect of troglitazone on body fat distribution in type 2 diabetic patients.Diabetes Care. 1999; 22: 908-912Crossref PubMed Scopus (242) Google Scholar). We that enhanced lipid to SF, but not VF, especially from fatty acids from the of lipoprotein-bound TAG by lipoprotein an important of fat redistribution induced by PPARγ as (4Laplante M. Sell H. MacNaul K.L. Richard D. Berger J.P. Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003; 52: 291-299Crossref PubMed Scopus (134) Google Scholar, M. Y. J. Berger J.P. Deshaies Y. of the depot of peroxisome proliferator-activated receptor on adipose tissue PubMed Scopus Google Scholar). of such fat redistribution by that the increased of to SF in with a depot-specific of glucose uptake and intracellular metabolism. Rosiglitazone increased SF glucose uptake in vivo and in vitro in the of insulin in part as a of the of the a study that of one PPARγ allele markedly WAT energy production and (6Anghel S.I. Bedu E. Vivier C.D. Descombes P. Desvergne B. Wahli W. Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma.J. Biol. Chem. 2007; 282: 29946-29957Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), PPARγ activation increased and conversion to and energy production in This is with the of glucose uptake, mRNA levels of enzymes of glycolysis, Krebs cycle, and Although of the genes were also upregulated in VF, the of the was than in SF, and it not in alterations of the corresponding metabolic other as of from glucose in SF by rosiglitazone be important not only to the of fatty acid esterification into TAG but also to the of WAT to of glucose toward glycogen and Although to a than oxidation, glucose in SF was also by an in tissue glycogen synthesis induced by rosiglitazone, as by the SF of glucose incorporation into glycogen and mRNA levels of and Although the of glucose into glycogen only a of WAT glucose metabolism, into the increase in SF induced by PPARγ to the in whole-body glucose homeostasis of of the fatty acid up from the de novo or from fatty acid esterification into TAG strongly an of glycerol the of glycerol in WAT, and as by the activity of its key were to be activated by rosiglitazone Li Y. metabolic activated in adipocytes by 2002; PubMed Scopus Google Scholar, P. E. J. 2 adipose expression of the Biol. PubMed Google M. M. Y. Deshaies Y. agonism adipose tissue expression of and the of to PubMed Scopus Google Scholar). by that rosiglitazone glucose conversion into TAG-glycerol in both VF and In vivo of TAG-glycerol synthesis with which the of glycerol synthesis from glucose both and a by rosiglitazone, an that was more in SF than VF, and in vitro PPARγ activation to the known of glycerol are stimulated in WAT, which the importance of PPARγ in the of fatty acid esterification and TAG synthesis. In SF, rosiglitazone also markedly enhanced in vitro glucose incorporation into the fatty acid of TAG, an that was associated with mRNA levels of and proteins involved in the of and which the in the fatty acid synthesis of fatty acid synthesis from glucose be the of of a regulator of R.A. of lipogenesis, the and of by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). increased in vitro fatty acid synthesis from glucose not translate into an in de novo lipogenesis in vivo as with This be the fatty acid from carbon to which glucose contributes in S.R. Glucose contribution to in vivo synthesis of and fatty acids in rats to a Full Text PDF PubMed Scopus Google Scholar). the of a in fatty acid synthesis in vivo in SF a in the contribution of other carbon acids, to glucose contribution and fatty acid synthesis for is activation by of WAT H. K. of in glucose uptake stimulated by the of in 2003; 52: PubMed Scopus Google Scholar), which and of fatty acid synthesis and oxidation by the 2002; PubMed Scopus Google Scholar), a key of the de novo fatty acid synthesis by levels and the pathway, rosiglitazone may the of the upregulated gene expression and glucose uptake into fatty acid synthesis in of the in vitro and in vivo and more the of in de novo fatty acid synthesis in vivo that SF induced by rosiglitazone is associated with an enhanced esterification of than fatty acids into TAG, which in turn is by of TAG-glycerol synthesis. the of fatty acids, of lipoprotein-bound TAG to be a major of fatty acids to SF, as by the tissue activity of rats with the mechanisms involved in the fat redistribution induced by rosiglitazone, an extensive analysis of the activities and mRNA levels of enzymes involved in TAG synthesis was and activities were markedly upregulated by rosiglitazone in both VF and SF, the of increased and lipin and and expression respectively. the activities only a depot-specific of rosiglitazone, with SF a than VF, an as of PPARγ agonism. for the activity in WAT, as in with J. M. J. K. as phosphatidate with tissue expression Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar). of with glucose with pioglitazone increased the expression of lipin but not lipin in subcutaneous adipose This was by increased insulin sensitivity A. N. B. J. K. expression is in adipose tissue of and with peroxisome proliferator-activated receptor PubMed Scopus Google Scholar). 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The effects of rosiglitazone in lipin expression in SF could part of its as an is to In study that the adipose depot of of PPARγ agonism for lipid metabolism to glucose The study an increase in glucose uptake and its intracellular energy and carbon to the of fatty acid esterification into TAG induced by rosiglitazone in The may be by the in SF of lipin expression and the an involvement of SF glucose metabolism in fat redistribution and in whole-body glucose homeostasis, which are of PPARγ agonism. The for the The are to H. for and for the lipogenesis and for the of and

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