Liver Peroxisome Proliferator-activated Receptor γ Contributes to Hepatic Steatosis, Triglyceride Clearance, and Regulation of Body Fat Mass

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that mediates the antidiabetic effects of thiazolidinediones. PPARγ is present in adipose tissue and becomes elevated in fatty livers, but the roles of specific tissues in thiazolidinedione actions are unclear. We studied the function of liver PPARγ in both lipoatrophic A-ZIP/F-1 (AZIP) and wild type mice. In AZIP mice, ablation of liver PPARγ reduced the hepatic steatosis but worsened the hyperlipidemia, triglyceride clearance, and muscle insulin resistance. Inactivation of AZIP liver PPARγ also abolished the hypoglycemic and hypolipidemic effects of rosiglitazone, demonstrating that, in the absence of adipose tissue, the liver is a primary and major site of thiazolidinedione action. In contrast, rosiglitazone remained effective in non-lipoatrophic mice lacking liver PPARγ, suggesting that adipose tissue is the major site of thiazolidinedione action in typical mice with adipose tissue. Interestingly, mice without liver PPARγ, but with adipose tissue, developed relative fat intolerance, increased adiposity, hyperlipidemia, and insulin resistance. Thus, liver PPARγ regulates triglyceride homeostasis, contributing to hepatic steatosis, but protecting other tissues from triglyceride accumulation and insulin resistance. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that mediates the antidiabetic effects of thiazolidinediones. PPARγ is present in adipose tissue and becomes elevated in fatty livers, but the roles of specific tissues in thiazolidinedione actions are unclear. We studied the function of liver PPARγ in both lipoatrophic A-ZIP/F-1 (AZIP) and wild type mice. In AZIP mice, ablation of liver PPARγ reduced the hepatic steatosis but worsened the hyperlipidemia, triglyceride clearance, and muscle insulin resistance. Inactivation of AZIP liver PPARγ also abolished the hypoglycemic and hypolipidemic effects of rosiglitazone, demonstrating that, in the absence of adipose tissue, the liver is a primary and major site of thiazolidinedione action. In contrast, rosiglitazone remained effective in non-lipoatrophic mice lacking liver PPARγ, suggesting that adipose tissue is the major site of thiazolidinedione action in typical mice with adipose tissue. Interestingly, mice without liver PPARγ, but with adipose tissue, developed relative fat intolerance, increased adiposity, hyperlipidemia, and insulin resistance. Thus, liver PPARγ regulates triglyceride homeostasis, contributing to hepatic steatosis, but protecting other tissues from triglyceride accumulation and insulin resistance. Peroxisome proliferator-activated receptor γ (PPARγ) 1The abbreviations used are: PPARγ, peroxisome proliferator-activated receptor γ; TZD, thiazolidinediones; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase; SREBP-1, sterol response element-binding protein; LDLR, low density lipoprotein receptor; WAT, white adipose tissue; BAT, brown adipose tissue. is a member of the nuclear hormone receptor superfamily. It can be activated by a variety of ligands, including fatty acids, eicosanoids (1Xu H.E. Lambert M.H. Montana V.G. Parks D.J. Blanchard S.G. Brown P.J. Sternbach D.D. Lehmann J.M. Wisely G.B. Willson T.M. Kliewer S.A. Milburn M.V. Mol. Cell. 1999; 3: 397-403Abstract Full Text Full Text PDF PubMed Scopus (967) Google Scholar), and 15-deoxy-Δ12,14-prostaglandin J2 (2Forman B.M. Tontonoz P. Chen J. Brun R.P. Spiegelman B.M. Evans R.M. Cell. 1995; 83: 803-812Abstract Full Text PDF PubMed Scopus (2731) Google Scholar). PPARγ is the primary molecular target of thiazolidinediones (TZDs), antidiabetic agents that act by increasing insulin sensitivity (reviewed in Ref. 3Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2096) Google Scholar). However, the target tissues and mechanisms by which TZDs increase insulin sensitivity are not well understood (4Foyt H.L. Ghazzi M.N. Hanley R.M. Saltiel A.R. Whitcomb R.W. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes mellitus: A Fundamental and Clinical Text. 2nd Ed. Lippincott Williams 106: 467-472Crossref PubMed Scopus (508) Google Scholar, 6Kersten S. Desvergne B. Wahli W. Nature. 2000; 405: 421-424Crossref PubMed Scopus (1665) Google Scholar). TZDs increase glucose utilization in muscle and, at higher doses, inhibit endogenous glucose production (largely a liver function) (7Inzucchi S.E. Maggs D.G. Spollett G.R. Page S.L. Rife F.S. Walton V. Shulman G.I. N. Engl. J. Med. 1998; 338: 867-872Crossref PubMed Scopus (722) Google Scholar, 8Maggs D.G. Buchanan T.A. Burant C.F. Cline G. Gumbiner B. Hsueh W.A. Inzucchi S. Kelley D. Nolan J. Olefsky J.M. Polonsky K.S. Silver D. Valiquett T.R. Shulman G.I. Ann. Intern. Med. 1998; 128: 176-185Crossref PubMed Scopus (289) Google Scholar, 9Mayerson A.B. Hundul R.S. Dufour S. Lebon V. Befroy D. Cline G. Enocksson S. Inzucchi S. Shulman G.I. Petersen K.F. Diabetes. 2002; 51: 797-802Crossref PubMed Scopus (554) Google Scholar). However, muscle and liver have low PPARγ levels. Several lines of evidence suggest that TZDs act directly on adipose tissue, with secondary effects in skeletal muscle and liver. 1) Adipose tissue is the only insulin-responsive tissue expressing high levels of PPARγ (10Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2000) Google Scholar, 11Chawla A. Schwarz E.J. Dimaculangan D.D. Lazar M.A. Endocrinology. 1994; 135: 798-800Crossref PubMed Scopus (617) Google Scholar, 12Vidal-Puig A. Jimenez-Linan M. Lowell B.B. Hamann A. Hu E. Spiegelman B. Flier J.S. Moller D.E. J. Clin. Invest. 1996; 97: 2553-2561Crossref PubMed Scopus (584) Google Scholar). 2) TZDs stimulate insulin action in cultured adipose tissue (13Berger J. Biswas C. Hayes N. Ventre J. Wu M. Doebber T.W. Endocrinology. 1996; 137: 1984-1990Crossref PubMed Scopus (31) Google Scholar) but not in isolated muscle (14Zierath J.R. Ryder J.W. Doebber T. Woods J. Wu M. Ventre J. Li Z. McCrary C. Berger J. Zhang B. Moller D.E. Endocrinology. 1998; 139: 5034-5041Crossref PubMed Google Scholar) or primary hepatocytes (15Jiang G. Dallas-Yang Q. Li Z. Szalkowski D. Liu F. Shen X. Wu M. Zhou G. Doebber T. Berger J. Moller D.E. Zhang B.B. Diabetes. 2002; 51: 2412-2419Crossref PubMed Scopus (96) Google Scholar). 3) PPARγ is essential for adipocyte differentiation (16Rosen E.D. Sarraf P. Troy A.E. Bradwin G. Moore K. Milstone D.S. Spiegelman B.M. Mortensen R.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, N. T. K. S. C. T. K. A. K. G. M. S. K. T. T. S. K. S. T. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of PPARγ and by TZDs stimulate adipocyte differentiation P. Hu E. Spiegelman B.M. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar), to accumulation of which are A. K. K. K. K. T. T. J. Clin. Invest. 1998; PubMed Scopus Google Scholar). in PPARγ in in adipose tissue but a of in liver and muscle J.M. Brown T.A. Willson T.M. Kliewer S.A. Endocrinology. PubMed Scopus Google Scholar). Thus, adipose tissue to be a target and the major site of action. Interestingly, in the absence of adipose tissue, TZDs have and in lipoatrophic with of fat E. J. N. N. J. D. D.E. J. A. A.E. J. Taylor S.I. Ann. Intern. Med. 2000; PubMed Scopus Google Scholar) and in a of C.F. S. K. T.A. J. J. S. Graves R.A. J. Clin. Invest. PubMed Scopus Google Scholar). In the A-ZIP/F-1 a of lipoatrophic J. M. D. B. E. T. M. C. Genes Dev. 1998; PubMed Scopus Google Scholar), the of on In AZIP mice, TZDs triglyceride levels but not the B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar). from the effects on muscle and with increased insulin sensitivity in skeletal muscle and insulin sensitivity in liver T. C. Chen M. Shulman Diabetes. PubMed Scopus Google Scholar). In contrast, in AZIP mice, rosiglitazone both and and M. suggest that PPARγ act directly on We on liver PPARγ a target of PPARγ levels are elevated in of the AZIP mice B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar, M. C. C. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. B. C. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of hepatic steatosis also increased liver PPARγ A. Jimenez-Linan M. Lowell B.B. Hamann A. Hu E. Spiegelman B. Flier J.S. Moller D.E. J. Clin. Invest. 1996; 97: 2553-2561Crossref PubMed Scopus (584) Google Scholar, C.F. S. K. T.A. J. J. S. Graves R.A. J. Clin. Invest. PubMed Scopus Google Scholar, M. M. K. B. B. J. 1999; Full Text Full Text PDF PubMed Google Scholar, P. C. J. A. P. T. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, R.A. K. A. C. Endocrinology. 2000; PubMed Google Scholar, M. E. J. Full Text Full Text PDF PubMed Scopus Google Scholar, E. M. C. B.M. Mol. PubMed Scopus Google Scholar), that increased PPARγ levels are a of liver. However, is the of PPARγ the steatosis or the steatosis the elevated PPARγ levels. of is to the of liver PPARγ in both wild type and mice. We used the to PPARγ and that liver PPARγ is of in wild type and lipoatrophic AZIP mice, to of hepatic steatosis in and in and mediates of the effects of rosiglitazone in lipoatrophic mice. by the and of the AZIP J. M. D. B. E. T. M. C. Genes Dev. 1998; PubMed Scopus Google Scholar), S. Lambert G. K. S. M. Mol. Cell. 2002; PubMed Scopus Google Scholar), and S. Liu B. A. D. B. LeRoith D. S. A. 1999; PubMed Scopus Google Scholar) mice have AZIP with and AZIP from the to to for for the AZIP and for both AZIP and mice studied for the which on the of the wild type or AZIP mice. used on a on and and J. PubMed Scopus Google Scholar) or high fat with and for in the and in and by isolated from liver of mice, with and S. Lambert G. K. S. M. Mol. Cell. 2002; PubMed Scopus Google Scholar). liver and by by B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar, M. C. C. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). K. M. Lambert G. J.M. B. J. Clin. Invest. PubMed Scopus Google Scholar). from liver isolated nuclear and with for by of from and of from nuclear to to and to the with a to to from or in the fatty and B. D. Shulman G.I. C. M. J. Clin. Invest. 2000; PubMed Scopus Google Scholar). and by and triglyceride M. C. C. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). for are F. S. B.B. S. J. Clin. Invest. 2000; PubMed Scopus Google Scholar, M. B. Shulman G.I. Diabetes. 2002; 51: PubMed Scopus Google Scholar) with a target insulin of and glucose of and production by in mice B. Diabetes. 2000; PubMed Scopus Google Scholar). In the increase in triglyceride triglyceride with J. J. PubMed Scopus Google Scholar, A. C. K. M. D.J. J. 1999; Full Text Full Text PDF PubMed Google Scholar). a for and with B. F. E. with Scholar). of a in and at and are is of in mice for and with of for from the and are S.E. or of of the PPARγ PPARγ mice by mice S. Lambert G. K. S. M. Mol. Cell. 2002; PubMed Scopus Google Scholar) with mice S. Liu B. A. D. B. LeRoith D. S. A. 1999; PubMed Scopus Google Scholar). wild type with lipoatrophic AZIP mice to AZIP mice lacking PPARγ in liver is in hepatocytes of the liver S. Liu B. A. D. B. LeRoith D. S. A. 1999; PubMed Scopus Google Scholar), by of Lambert G. J.M. Mol. Cell. PubMed Scopus Google Scholar). mice at of and that of the PPARγ the in both and AZIP and is to be from which not the C. M. Chen J.M. J. M.A. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the of liver PPARγ levels. B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar, M. C. C. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), the AZIP PPARγ the a and of PPARγ levels in the and AZIP mice, that in the AZIP liver of the PPARγ is a from the wild type PPARγ in the liver K. M. Lambert G. J.M. B. J. Clin. Invest. PubMed Scopus Google Scholar). PPARγ a which is to and or which to be S. Lambert G. K. S. M. Mol. Cell. 2002; PubMed Scopus Google Scholar). that the AZIP liver to the liver of the E. M. C. B.M. Mol. PubMed Scopus Google Scholar). In the AZIP mice, levels levels also the of the with that in the mice. In to lipoatrophic mice, liver which not by the suggest that in the wild type liver of the PPARγ is by in the liver of the AZIP mice hepatocytes is the major of PPARγ of PPARγ in the AZIP of liver PPARγ not a major in non-lipoatrophic mice, with on liver liver in triglyceride or or fatty acid levels and not In contrast, of liver PPARγ the AZIP increased and liver of the AZIP mice reduced by liver PPARγ ablation a and without on other in liver with a in liver triglyceride in triglyceride and levels of in fatty acid to suggesting a for liver PPARγ in triglyceride and and AZIP mice also with the AZIP mice, but only at the of in not of the of in and AZIP mice and of PPARγ of in for and AZIP for PPARγ and for PPARγ and for and AZIP for and AZIP for PPARγ and for and AZIP for PPARγ and for PPARγ and for PPARγ and for PPARγ and for PPARγ and for PPARγ and for and AZIP for and AZIP for and AZIP for PPARγ and for and AZIP for PPARγ and for PPARγ and in a Inactivation of PPARγ reduced triglyceride in the AZIP mice be to triglyceride levels. However, of liver PPARγ increased the elevated triglyceride levels in the AZIP mice suggesting a in triglyceride directly triglyceride levels In mice, at at and to levels. In AZIP mice, to at demonstrating of triglyceride in the absence of adipose tissue. AZIP mice fat with at and elevated the Thus, of liver PPARγ the of AZIP mice by of triglyceride Interestingly, mice not have elevated triglyceride a in triglyceride the the higher in the in the mice suggest that liver PPARγ to triglyceride in wild non-lipoatrophic mice. of PPARγ in the AZIP high triglyceride levels with increased muscle triglyceride and insulin triglyceride levels in skeletal of liver PPARγ a increase in muscle triglyceride levels in the AZIP mice to We not in glucose or insulin levels in the AZIP and AZIP in both glucose levels and insulin levels higher the and However, glucose higher in the AZIP with the AZIP mice and suggesting that of liver PPARγ lipoatrophic mice glucose homeostasis, and In mice, of PPARγ in liver on of the In AZIP mice, endogenous glucose production by insulin in the hepatic insulin resistance. of liver PPARγ not in endogenous glucose production or by suggesting that the used liver insulin in the AZIP and AZIP mice In contrast, of PPARγ in liver muscle insulin In AZIP mice, muscle glucose of the but only in the AZIP mice that of liver PPARγ muscle insulin in lipoatrophic mice in the of not have a major only a of triglyceride of and mice of liver PPARγ on liver or a and and not However, the mice adipose tissue in triglyceride in mice with with and the of the mice also elevated glucose and insulin insulin and in the mice with a increase in and a in levels Thus, in non-lipoatrophic mice, of liver PPARγ fat and with hyperlipidemia, and insulin resistance. can be also in mice, the effects of the and on adipose tissue in and mice and mice the and mice on the a of and In contrast, only on the mice the in of the of in However, the the mice on the the of levels with the Thus, the a to in PPARγ mice. that hepatic PPARγ a in of triglyceride liver and other contributing to of fat and glucose in non-lipoatrophic mice. PPARγ Genes in the effects of liver PPARγ target levels a AZIP mice have increased levels of including PPARγ, sterol response element-binding fatty acid acetyl-CoA and stearoyl-CoA B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar). PPARγ ablation reduced the FAS, ACC, and levels and of SREBP-1, a of not suggesting that PPARγ of or to AZIP mice have elevated levels of liver which a lipoprotein acid of liver PPARγ reduced levels by only and in the AZIP and mice, density lipoprotein receptor levels reduced by but only in the AZIP mice. In contrast, hepatic and levels increased in both and the AZIP mice. and low density lipoprotein receptor in and not to be by AZIP or PPARγ of other triglyceride fatty not by ablation of liver AZIP also have elevated levels of adipose and adipose fatty and is a in T. G. E.J. C. J. Full Text PDF PubMed Google Scholar), is a fatty in PubMed Scopus Google Scholar). levels of both and reduced in the AZIP mice, suggesting that liver PPARγ also to of and the PPARγ for in the AZIP the of liver PPARγ to the antidiabetic effects of rosiglitazone, a PPARγ rosiglitazone effects in the lipoatrophic AZIP mice B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar), rosiglitazone increased liver and hepatic and in the AZIP mice In elevated and liver effects abolished in the AZIP mice, demonstrating that are by liver PPARγ rosiglitazone not glucose and insulin levels in AZIP mice with a B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar). mice of of the with a in glucose and increase in insulin and and of liver PPARγ abolished the of rosiglitazone in AZIP mice. that, in the absence of adipose tissue, liver PPARγ mediates triglyceride and to the hypoglycemic effects of Interestingly, rosiglitazone a in fatty acid levels in both AZIP and AZIP mice, suggesting that tissues other that liver and fat to on liver levels in mice In contrast, in the AZIP mice, rosiglitazone increased levels of ACC, FAS, SCD1, and and not effects of rosiglitazone abolished in the AZIP mice, suggesting a for liver PPARγ in of in fatty acid and PPARγ for in liver PPARγ is essential for the antidiabetic effects of rosiglitazone in a typical with adipose tissue. and mice with a high fat of high fat the and mice elevated glucose and insulin suggesting a of insulin a and to be higher in mice without liver PPARγ fatty not and and mice to rosiglitazone by and fatty acid levels and by glucose and fat and not Thus, in non-lipoatrophic mice liver PPARγ is not for the antidiabetic and hypolipidemic effects of In both and mice, rosiglitazone increased adipose tissue and reduced liver and steatosis and and not are with the that the primary increased triglyceride in adipose tissue, with a secondary in liver triglyceride levels. increased levels in both and mice and the increase in only in the mice. Thus, rosiglitazone effects in the and mice, demonstrating that in non-lipoatrophic mice liver PPARγ to the effects of suggest that adipose tissue is the major site of thiazolidinedione action in typical mice with adipose tissue. that liver PPARγ to triglyceride homeostasis, both triglyceride and the A for hepatic PPARγ not of low in liver. Inactivation of liver PPARγ reduced hepatic steatosis in both lipoatrophic AZIP mice and mice with In the AZIP with reduced triglyceride from the liver and of FAS, ACC, and SCD1, suggesting that in lipoatrophic mice liver PPARγ hepatic steatosis by Interestingly, of hepatic steatosis not the of the AZIP mice, the triglyceride clearance, hyperlipidemia, and muscle insulin resistance. Inactivation of PPARγ in liver of the mice effects K. M. Lambert G. J.M. B. J. Clin. Invest. PubMed Scopus Google Scholar). suggest that hepatic steatosis not only a of increased triglyceride production but is also of by liver. of hepatic steatosis and of triglyceride in the AZIP on C. M. B. C. J. Full Text Full Text PDF PubMed Scopus Google Scholar). AZIP mice have high triglyceride and fatty AZIP mice have low triglyceride but liver. Thus, is that the effects of liver PPARγ be by of the mechanisms contributing to hepatic steatosis from the in hepatic steatosis also in the by of P. M. A. W. J.M. J.M. 2002; PubMed Scopus Google Scholar) or of N. T. T. T. M. S. K. J. K. T. S. N. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). are that including FAS, ACC, and Brown J. Clin. Invest. 2002; PubMed Scopus Google Scholar). to PPARγ, levels are elevated in B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar, J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). mice the of have fatty a for in of the steatosis Brown J. Clin. Invest. 1996; PubMed Scopus Google Scholar, Brown J. Clin. Invest. PubMed Scopus Google Scholar). of PPARγ not that PPARγ directly to hepatic steatosis, of or in with Interestingly, of PPARγ and both reduced and triglyceride in liver N. T. T. T. M. S. K. J. K. T. S. N. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), of triglyceride only PPARγ suggest that the of hepatic PPARγ in of by liver is not with target and molecular mechanisms by which liver PPARγ mediates of liver PPARγ a in levels in the mice. is in with a S. K. P. V. J. Full Text Full Text PDF PubMed Scopus Google Scholar) that of increased levels in of the mice. Thus, receptor be of the of by liver. a lipoprotein acid is PPARγ increase levels in including and R.A. K. A. C. Endocrinology. 2000; PubMed Google Scholar, S. Lambert G. K. S. M. Mol. Cell. 2002; PubMed Scopus Google Scholar, Liu F. G. Li Z. J. M. J.R. A. A. D.J. Doebber T.W. Berger J. A. Moller D.E. Zhang B.B. Endocrinology. 2002; PubMed Scopus Google Scholar, Liu S. M. R.A. C. Tontonoz P. P.J. Mol. PubMed Scopus Google Scholar, A. D. Tontonoz P. Evans R.M. Med. PubMed Scopus Google Scholar, E.D. F. D. Milstone D.S. Mortensen R.M. Spiegelman B.M. Med. PubMed Scopus Google Scholar). of function of hypolipidemic and insulin effects of in N. V. V. V. M. T.W. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). However, of in mice reduced fatty acid adipose tissue, skeletal and but on liver M. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the of in liver unclear. the is that liver PPARγ ablation increased adipose tissue and insulin in non-lipoatrophic mice. is in to the for PPARγ for adipose tissue (16Rosen E.D. Sarraf P. Troy A.E. Bradwin G. Moore K. Milstone D.S. Spiegelman B.M. Mortensen R.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, N. T. K. S. C. T. K. A. K. G. M. S. K. T. T. S. K. S. T. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, P. A. Evans R.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and the that with have PPARγ M. M. J.W. M.A. Williams S. Nature. 1999; PubMed Scopus Google Scholar, A. J. Clin. 2002; PubMed Scopus Google Scholar, R.A. C. T. Diabetes. 2002; 51: PubMed Scopus Google Scholar). mice for a PPARγ are from high fat and have increased insulin sensitivity N. T. K. S. C. T. K. A. K. G. M. S. K. T. T. S. K. S. T. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Evans R.M. Olefsky J.M. J. Clin. Invest. 2000; PubMed Scopus Google Scholar). A for the by PPARγ from that PPARγ ablation the of the liver to the in non-lipoatrophic mice, the that in the of reduced hepatic are in other adipose tissue and insulin resistance. of the liver PPARγ mice is on and that with the of It well that PPARγ including act insulin in and but the and relative of target tissues are J.M. J. Clin. Invest. 2000; 106: 467-472Crossref PubMed Scopus (508) Google Scholar). that TZDs act directly on adipose tissue, with secondary effects in skeletal muscle and liver. of insulin sensitivity in and adipose tissue (7Inzucchi S.E. Maggs D.G. Spollett G.R. Page S.L. Rife F.S. Walton V. Shulman G.I. N. Engl. J. Med. 1998; 338: 867-872Crossref PubMed Scopus (722) Google Scholar, 8Maggs D.G. Buchanan T.A. Burant C.F. Cline G. Gumbiner B. Hsueh W.A. Inzucchi S. Kelley D. Nolan J. Olefsky J.M. Polonsky K.S. Silver D. Valiquett T.R. Shulman G.I. Ann. Intern. Med. 1998; 128: 176-185Crossref PubMed Scopus (289) Google Scholar, 9Mayerson A.B. Hundul R.S. Dufour S. Lebon V. Befroy D. Cline G. Enocksson S. Inzucchi S. Shulman G.I. Petersen K.F. Diabetes. 2002; 51: 797-802Crossref PubMed Scopus (554) Google Scholar) is by increase of E. J. N. N. J. D. D.E. J. A. A.E. J. Taylor S.I. Ann. Intern. Med. 2000; PubMed Scopus Google Scholar, K. Diabetes 1999; PubMed Scopus Google Scholar, K. J. N. Diabetes 1999; PubMed Scopus Google Scholar). insulin in muscle and adipose tissue be by PPARγ a of insulin action in liver (15Jiang G. Dallas-Yang Q. Li Z. Szalkowski D. Liu F. Shen X. Wu M. Zhou G. Doebber T. Berger J. Moller D.E. Zhang B.B. Diabetes. 2002; 51: 2412-2419Crossref PubMed Scopus (96) Google Scholar) and higher D.G. Buchanan T.A. Burant C.F. Cline G. Gumbiner B. Hsueh W.A. Inzucchi S. Kelley D. Nolan J. Olefsky J.M. Polonsky K.S. Silver D. Valiquett T.R. Shulman G.I. Ann. Intern. Med. 1998; 128: 176-185Crossref PubMed Scopus (289) Google Scholar), with adipose tissue ablation of liver PPARγ not the of rosiglitazone PPARγ mice also response to rosiglitazone M. F. Diabetes. Scopus Google Scholar). that in a typical liver PPARγ muscle PPARγ are essential for the effects of rosiglitazone, suggesting that TZDs act adipose tissue. In contrast, in the absence of adipose tissue, liver becomes the major site of action. of liver PPARγ abolished of the effects of rosiglitazone in the AZIP including a in glucose and triglyceride and increase in hepatic triglyceride Thus, mechanisms by which TZDs in lipoatrophic mice of triglyceride from the the liver and increased fat TZDs in lipoatrophic mice B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar) and E. J. N. N. J. D. D.E. J. A. A.E. J. Taylor S.I. Ann. Intern. Med. 2000; PubMed Scopus Google Scholar), but which tissue is for is unclear. is to rosiglitazone hepatic in a that liver PPARγ is not for of fatty by rosiglitazone that tissues other that liver and adipose also to fat It is to that of in lipoatrophic mice on In AZIP mice, rosiglitazone triglyceride but on B. J. C. E. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar), of the effects of muscle and liver T. C. Chen M. Shulman Diabetes. PubMed Scopus Google Scholar). In contrast, AZIP mice both and to a of C.F. S. K. T.A. J. J. S. Graves R.A. J. Clin. Invest. PubMed Scopus Google Scholar). In in the AZIP mice of rosiglitazone but increased insulin of of the lipoatrophic mice to is not the of the be to the of in a of E. Taylor S.I. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Med. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the and hepatic We are of PPARγ levels in liver from In typical type rosiglitazone reduced hepatic triglyceride A.B. Hundul R.S. Dufour S. Lebon V. Befroy D. Cline G. Enocksson S. Inzucchi S. Shulman G.I. Petersen K.F. Diabetes. 2002; 51: 797-802Crossref PubMed Scopus (554) Google Scholar). also in liver in a of with increase in adipose E. J. N. N. J. D. D.E. J. A. A.E. J. Taylor S.I. Ann. Intern. Med. 2000; PubMed Scopus Google Scholar). It is that of hepatic steatosis with is a to the by in M.H. Mol. 1998; 53: PubMed Scopus Google Scholar, S. Nature. PubMed Scopus Google Scholar). However, are to the of in with We P. for for and P. D. D. and A. for on the