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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1997 December 1; 100(11): 2900–2908.
PMCID: PMC508497

Troglitazone action is independent of adipose tissue.


We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue.

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  • DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. [PubMed]
  • Polonsky KS. Lilly Lecture 1994. The beta-cell in diabetes: from molecular genetics to clinical research. Diabetes. 1995 Jun;44(6):705–717. [PubMed]
  • Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997 Jan;46(1):3–10. [PubMed]
  • Reaven GM. The fourth musketeer--from Alexandre Dumas to Claude Bernard. Diabetologia. 1995 Jan;38(1):3–13. [PubMed]
  • Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996 Dec;45(12):1661–1669. [PubMed]
  • Sreenan S, Sturis J, Pugh W, Burant CF, Polonsky KS. Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol. 1996 Oct;271(4 Pt 1):E742–E747. [PubMed]
  • Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes. 1997 Mar;46(3):433–439. [PubMed]
  • Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell. 1996 Nov 1;87(3):377–389. [PubMed]
  • Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. [PubMed]
  • Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM. The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem. 1996 Feb 2;39(3):665–668. [PubMed]
  • Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994 May 15;8(10):1224–1234. [PubMed]
  • Tai TA, Jennermann C, Brown KK, Oliver BB, MacGinnitie MA, Wilkison WO, Brown HR, Lehmann JM, Kliewer SA, Morris DC, et al. Activation of the nuclear receptor peroxisome proliferator-activated receptor gamma promotes brown adipocyte differentiation. J Biol Chem. 1996 Nov 22;271(47):29909–29914. [PubMed]
  • Zhu Y, Alvares K, Huang Q, Rao MS, Reddy JK. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem. 1993 Dec 25;268(36):26817–26820. [PubMed]
  • Kletzien RF, Clarke SD, Ulrich RG. Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol Pharmacol. 1992 Feb;41(2):393–398. [PubMed]
  • Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994 Nov;43(11):1271–1278. [PubMed]
  • Ross SR, Graves RA, Spiegelman BM. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity. Genes Dev. 1993 Jul;7(7B):1318–1324. [PubMed]
  • Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, Sun X, Polonsky KS, Bell GI. Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes. 1995 Dec;44(12):1447–1457. [PubMed]
  • Sturis J, Pugh WL, Tang J, Polonsky KS. Prevention of diabetes does not completely prevent insulin secretory defects in the ZDF rat. Am J Physiol. 1995 Oct;269(4 Pt 1):E786–E792. [PubMed]
  • Nakamura K, Handa S. Coomassie brilliant blue staining of lipids on thin-layer plates. Anal Biochem. 1984 Nov 1;142(2):406–410. [PubMed]
  • Burant CF, Lemmon SK, Treutelaar MK, Buse MG. Insulin resistance of denervated rat muscle: a model for impaired receptor-function coupling. Am J Physiol. 1984 Nov;247(5 Pt 1):E657–E666. [PubMed]
  • Laborda J. 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. Nucleic Acids Res. 1991 Jul 25;19(14):3998–3998. [PMC free article] [PubMed]
  • De Vos P, Lefebvre AM, Miller SG, Guerre-Millo M, Wong K, Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest. 1996 Aug 15;98(4):1004–1009. [PMC free article] [PubMed]
  • Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996 Jan;137(1):354–366. [PubMed]
  • Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996 Jun 15;97(12):2859–2865. [PMC free article] [PubMed]
  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. [PubMed]
  • Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997 Mar;15(3):269–272. [PubMed]
  • Vidal-Puig A, Jimenez-Liñan M, Lowell BB, Hamann A, Hu E, Spiegelman B, Flier JS, Moller DE. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J Clin Invest. 1996 Jun 1;97(11):2553–2561. [PMC free article] [PubMed]
  • Yki-Järvinen H. Glucose toxicity. Endocr Rev. 1992 Aug;13(3):415–431. [PubMed]
  • Castle CK, Colca JR, Melchior GW. Lipoprotein profile characterization of the KKA(y) mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing agent pioglitazone. Arterioscler Thromb. 1993 Feb;13(2):302–309. [PubMed]
  • Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes. 1991 Feb;40(2):280–289. [PubMed]
  • Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637–4641. [PubMed]
  • Levak-Frank S, Radner H, Walsh A, Stollberger R, Knipping G, Hoefler G, Sattler W, Weinstock PH, Breslow JL, Zechner R. Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest. 1995 Aug;96(2):976–986. [PMC free article] [PubMed]
  • Desbois-Mouthon C, Magré J, Amselem S, Reynet C, Blivet MJ, Goossens M, Capeau J, Besmond C. Lipoatrophic diabetes: genetic exclusion of the insulin receptor gene. J Clin Endocrinol Metab. 1995 Jan;80(1):314–319. [PubMed]
  • Robert JJ, Magre J, Reynet C, Darmaun D, Picard J, Capeau J. In vivo and in vitro characterization of insulin resistance in three cases of lipoatrophic diabetes. Diabete Metab. 1990 May-Jun;16(3):240–247. [PubMed]
  • Inoue I, Takahashi K, Katayama S, Harada Y, Negishi K, Itabashi A, Ishii J. Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats. Metabolism. 1995 Dec;44(12):1626–1630. [PubMed]

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