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

J Clin Invest. 2003 Mar;111(5):737-47. doi: 10.1172/JCI17223.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Fatty Acids, Nonesterified / blood
  • Fatty Liver / etiology*
  • Fatty Liver / 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


  • 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