Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes
Kimihiko Matsusue, Martin Haluzik, Gilles Lambert, Sun-Hee Yim, Oksana Gavrilova, Jerrold M. Ward, Bryan Brewer Jr., Marc L. Reitman, Frank J. Gonzalez
Kimihiko Matsusue, Martin Haluzik, Gilles Lambert, Sun-Hee Yim, Oksana Gavrilova, Jerrold M. Ward, Bryan Brewer Jr., Marc L. Reitman, Frank J. Gonzalez
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Article Metabolism

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

Abstract

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

Authors

Kimihiko Matsusue, Martin Haluzik, Gilles Lambert, Sun-Hee Yim, Oksana Gavrilova, Jerrold M. Ward, Bryan Brewer Jr., Marc L. Reitman, Frank J. Gonzalez

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Figure 4

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Effect of PPARγ deficiency on the catabolism of serum TG in the ob/ob mo...
Effect of PPARγ deficiency on the catabolism of serum TG in the ob/ob mouse. Lipoproteins were separated from 60 μl of pooled mouse plasma samples (n = 6 for each genotype) by FPLC. The concentration of TG (a) and cholesterol (b) in each eluted fraction is indicated on the y axis. Inset: immunoblot analysis of apoB, apoE, apoA-I, and apoA-II contained within the VLDL (V), LDL (L), and HDL (H) top fractions from each mouse genotype. (c) Measurement of serum TG after gavage with oil. The clearance rate of exogenous TG was measured in mice fasted for 4 hours as described in Methods. (d and e) Measurement of plasma lipase activities (d) and VLDL export rates (e). In d, for ob/ob-PPARγ(fl/fl)AlbCre– mice, n = 7; ob/ob-PPARγ(fl/fl)AlbCre+, n = 10. In e, for ob/ob-PPARγ(fl/fl)AlbCre–, n = 7; ob/ob-PPARγ(fl/fl)AlbCre+, n = 6. Each assay was performed as described in Methods. LPL, lipoprotein lipase; HL, hepatic lipase. (f) Northern blotting for hepatic lipase. The Northern blot was performed as described in the legend to Figure 3. All data are mean ± SE.*P < 0.01, Cre– vs. Cre+ mice.