Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes
Kimihiko Matsusue, … , Marc L. Reitman, Frank J. Gonzalez
Kimihiko Matsusue, … , Marc L. Reitman, Frank J. Gonzalez
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):737-747. https://doi.org/10.1172/JCI17223.
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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 5

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Effect of PPARγ deficiency on glucose homeostasis in the ob/ob mouse. (a...
Effect of PPARγ deficiency on glucose homeostasis in the ob/ob mouse. (a) Blood glucose concentrations were measured in 10-week-old mice after no fasting and after 6 hours or 24 hours of fasting. For OB/OB-PPARγ(fl/fl)AlbCre– mice, n = 15; OB/OB-PPARγ(fl/fl)AlbCre+, n = 16; ob/ob-PPARγ(fl/fl)AlbCre–, n = 16; and ob/ob-PPARγ(fl/fl)AlbCre+, n = 11. (b and c) Glucose tolerance test. 10-week-old (b) and 6-week-old (c) mice were injected with glucose (2 mg/g). For 10-week-old mice, OB/OB-PPARγ(fl/fl)AlbCre– mice, n = 8; OB/OB-PPARγ(fl/fl)AlbCre+, n = 9; ob/ob-PPARγ(fl/fl)AlbCre–, n = 19; and ob/ob-PPARγ(fl/fl)AlbCre+, n = 15. For 6-week-old mice, ob/ob-PPARγ(fl/fl)AlbCre–, n = 9; and ob/ob-PPARγ(fl/fl)AlbCre+, n = 8. (d and e) Effect of rosiglitazone on glucose and insulin levels. Both of these measurements were performed using the same samples. For 20-week-old mice, ob/ob-PPARγ(fl/fl)AlbCre–, n = 13; ob/ob-PPARγ(fl/fl)AlbCre+, n = 8. For 7-week-old mice, ob/ob-PPARγ(fl/fl)AlbCre–, n = 11; ob/ob-PPARγ(fl/fl)AlbCre+, n = 6. (f–i) Hyperinsulinemic-euglycemic clamp. Measurements of (f) whole-body glucose uptake (g) suppression of basal endogenous glucose production (EGP) (h) white adipose glucose uptake, and (i) muscle glucose uptake. Male 5-week-old mice were used in this experiment. For ob/ob-PPARγ(fl/fl)AlbCre– mice, n = 4; ob/ob-PPARγ(fl/fl)AlbCre+, n = 6. All data are mean ± SE. *P < 0.05, Cre – vs. Cre+ mice. (j–o) Effect of rosiglitazone on glucose levels (j and l), glucose tolerance (k), insulin levels (m), FFA (n), and TG (o) in ob/ob mice. The legend to Figure 2l describes the conditions for rosiglitazone treatment in the glucose analysis studies (j). For rosiglitazone-treated mice: ob/ob-PPARγ(fl/fl)AlbCre–, n = 11; ob/ob-PPARγ(fl/fl)AlbCre+, n = 4. For control mice: ob/ob-PPARγ(fl/fl)AlbCre–, n = 10; ob/ob-PPARγ(fl/fl)AlbCre+, n = 4. All data are mean ± SE. *P < 0.05, **P < 0.01, ***P < 0.001, rosiglitazone-treated vs. control Cre– mice. †P < 0.05, ††P < 0.01, †††P < 0.001, rosiglitazone-treated vs. control Cre+ mice. Rosi, rosiglitazone; Cont, control.