Home LiteratureArticle Details
PMID: 12618528 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.

The Journal of clinical investigation ·Vol. 111 ·No. 5 ·2003-03-00 ·Pages 737-47

Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B, Reitman ML, Gonzalez FJ

Abstract

To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a PPARgamma liver-null mouse on an ob/ob background, ob/ob-PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele, PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically decreased triglyceride (TG) content compared with equivalent mice lacking the AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice, and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice. Rosiglitazone treatment exacerbated the fatty liver in ob/ob-PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice; there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The deficiency of hepatic PPARgamma further aggravated the severity of diabetes in ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data indicate that hepatic PPARgamma plays a critical role in the regulation of TG content and in the homeostasis of blood glucose and insulin resistance in steatotic diabetic mice.

MeSH Terms
Animals Blood Glucose/analysis Fatty Acids, Nonesterified/blood Fatty Liver/etiology,therapy Hyperglycemia/etiology Insulin Resistance Leptin/deficiency Lipoprotein Lipase/metabolism Lipoproteins, VLDL/metabolism Liver/physiology Mice Mice, Inbred C57BL Mice, Obese Receptors, Cytoplasmic and Nuclear/physiology Receptors, LDL/metabolism Receptors, Leptin Rosiglitazone Thiazoles/therapeutic use Thiazolidinediones Transcription Factors/physiology Triglycerides/metabolism
Chemicals
Blood Glucose Fatty Acids, Nonesterified Leptin Lipoproteins, VLDL Receptors, Cytoplasmic and Nuclear Receptors, LDL Receptors, Leptin Thiazoles Thiazolidinediones Transcription Factors Triglycerides leptin receptor, mouse Rosiglitazone Lipoprotein Lipase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Matsusue Kimihiko
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Frederick, Maryland 20892, USA.
Haluzik Martin
Lambert Gilles
Yim Sun-Hee
Gavrilova Oksana
Ward Jerrold M
Brewer Bryan
Reitman Marc L
Gonzalez Frank J
References (54)
54 references, click to expand
  1. Transcriptional profiling reveals global defects in energy metabolism, lipoprotein, and bile acid synthesis and transport with reversal by leptin treatment in ob/ob mouse liver.
    J Biol Chem. 2001 Dec 28;276(52):49066-76 PMID: 11551957
  2. A rapid method of total lipid extraction and purification.
    Can J Biochem Physiol. 1959 Aug;37(8):911-7 PMID: 13671378
  3. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway.
    Genes Dev. 2002 Jan 1;16(1):22-6 PMID: 11782441
  4. Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux.
    Mol Cell Biol. 2002 Apr;22(8):2607-19 PMID: 11909955
  5. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.
    J Clin Invest. 2002 May;109(9):1125-31 PMID: 11994399
  6. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice.
    J Clin Invest. 2002 May;109(10):1381-9 PMID: 12021254
  7. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice.
    J Biol Chem. 2002 May 31;277(22):19353-7 PMID: 11923308
  8. PPAR(gamma) and glucose homeostasis.
    Annu Rev Nutr. 2002;22:167-97 PMID: 12055342
  9. PPARs: transcription factors controlling lipid and lipoprotein metabolism.
    Ann N Y Acad Sci. 2002 Jun;967:7-18 PMID: 12079830
  10. Adrenalectomy improves diabetes in A-ZIP/F-1 lipoatrophic mice by increasing both liver and muscle insulin sensitivity.
    Diabetes. 2002 Jul;51(7):2113-8 PMID: 12086940
  11. PPARs: transcriptional effectors of fatty acids and their derivatives.
    Cell Mol Life Sci. 2002 May;59(5):790-8 PMID: 12088279
  12. PPAR gamma is required for placental, cardiac, and adipose tissue development.
    Mol Cell. 1999 Oct;4(4):585-95 PMID: 10549290
  13. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.
    Mol Cell. 1999 Oct;4(4):597-609 PMID: 10549291
  14. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro.
    Mol Cell. 1999 Oct;4(4):611-7 PMID: 10549292
  15. Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis.
    Carcinogenesis. 2000 Apr;21(4):823-6 PMID: 10753222
  16. Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specific agonists in PPARalpha-null mice.
    Mol Pharmacol. 2000 Sep;58(3):470-6 PMID: 10953038
  17. Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice.
    Endocrinology. 2000 Nov;141(11):4021-31 PMID: 11089532
  18. Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones.
    J Clin Invest. 2000 Nov;106(10):1221-8 PMID: 11086023
  19. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.
    Genes Dev. 2000 Nov 15;14(22):2819-30 PMID: 11090130
  20. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.
    Mol Cell Biol. 2001 Feb;21(4):1393-403 PMID: 11158324
  21. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.
    Mol Cell. 2001 Jan;7(1):161-71 PMID: 11172721
  22. Insulin resistance and its treatment by thiazolidinediones.
    Recent Prog Horm Res. 2001;56:265-94 PMID: 11237217
  23. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter.
    Mol Cell Biol. 2001 May;21(9):2991-3000 PMID: 11287605
  24. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice.
    J Clin Invest. 2001 Jul;108(2):303-9 PMID: 11457883
  25. Diabetic KKAy mice exhibit increased hepatic PPARgamma1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones.
    J Hepatol. 2001 Jul;35(1):17-23 PMID: 11495036
  26. Peroxisome proliferator-activated receptors in macrophage biology: friend or foe?
    Curr Opin Lipidol. 2001 Oct;12(5):519-27 PMID: 11561171
  27. PPAR gamma agonists in type 2 diabetes: how far have we come in 'preventing the inevitable'? A review of the metabolic effects of rosiglitazone.
    Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S34-43 PMID: 11685828
  28. Hepatic over-expression of peroxisome proliferator activated receptor gamma2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus.
    Mol Cell Biochem. 2001 Aug;224(1-2):29-37 PMID: 11693197
  29. Enhancement of the aquaporin adipose gene expression by a peroxisome proliferator-activated receptor gamma.
    J Biol Chem. 2001 Dec 21;276(51):48572-9 PMID: 11679588
  30. Hepatic lipase: a pro- or anti-atherogenic protein?
    J Lipid Res. 2002 Sep;43(9):1352-62 PMID: 12235167
  31. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression.
    J Biol Chem. 2003 Jan 3;278(1):498-505 PMID: 12401792
  32. Isolation and subfractionation on ficoll gradients of adult rat hepatocytes. Size, morphology, and biochemical characteristics of cell fractions.
    J Cell Biol. 1975 Jul;66(1):1-22 PMID: 167028
  33. Human adipose tissue lipoprotein lipase: changes with feeding and relation to postheparin plasma enzyme.
    Am J Physiol. 1985 Jul;249(1 Pt 1):E107-14 PMID: 4014455
  34. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation.
    Endocrinology. 1990 Oct;127(4):1580-9 PMID: 1698143
  35. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation.
    Endocrinology. 1994 Aug;135(2):798-800 PMID: 8033830
  36. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.
    Genes Dev. 1994 May 15;8(10):1224-34 PMID: 7926726
  37. The peroxisome proliferator activated receptor regulates malic enzyme gene expression.
    J Biol Chem. 1994 Oct 28;269(43):26754-8 PMID: 7929410
  38. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).
    J Biol Chem. 1995 Jun 2;270(22):12953-6 PMID: 7768881
  39. SREBP-1 mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I.
    J Biol Chem. 1996 Mar 22;271(12):7128-33 PMID: 8636148
  40. Mechanism of free fatty acid-induced insulin resistance in humans.
    J Clin Invest. 1996 Jun 15;97(12):2859-65 PMID: 8675698
  41. Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.
    Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9443-8 PMID: 8790349
  42. The organization, promoter analysis, and expression of the human PPARgamma gene.
    J Biol Chem. 1997 Jul 25;272(30):18779-89 PMID: 9228052
  43. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.
    J Clin Invest. 1997 Oct 15;100(8):2115-24 PMID: 9329978
  44. Troglitazone action is independent of adipose tissue.
    J Clin Invest. 1997 Dec 1;100(11):2900-8 PMID: 9389757
  45. PPARgamma and colorectal carcinoma: conflicts in a nuclear family.
    Nat Med. 1998 Sep;4(9):1004-5 PMID: 9734386
  46. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice.
    Nat Med. 1998 Sep;4(9):1053-7 PMID: 9734399
  47. Activators of the nuclear receptor PPARgamma enhance colon polyp formation.
    Nat Med. 1998 Sep;4(9):1058-61 PMID: 9734400
  48. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.
    J Biol Chem. 1999 Jan 1;274(1):305-15 PMID: 9867845
  49. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.
    J Clin Invest. 1999 Jan;103(2):253-9 PMID: 9916137
  50. Fatty acids, lipotoxicity and insulin secretion.
    Diabetologia. 1999 Feb;42(2):128-38 PMID: 10064091
  51. Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes.
    Diabetes. 1999 Apr;48(4):699-705 PMID: 10102684
  52. Normal growth and development in the absence of hepatic insulin-like growth factor I.
    Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7324-9 PMID: 10377413
  53. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.
    J Biol Chem. 1999 Oct 15;274(42):30028-32 PMID: 10514488
  54. Unique ability of troglitazone to up-regulate peroxisome proliferator-activated receptor-gamma expression in hepatocytes.
    J Pharmacol Exp Ther. 2002 Jan;300(1):72-7 PMID: 11752099
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI17223
Published
2003-03-00
Pages
737-47
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151902
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI17223 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2