Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones

Andrew W. Norris, Lihong Chen, Simon J. Fisher, Ildiko Szanto, Michael Ristow, Alison C. Jozsi, Michael F. Hirshman, Evan D. Rosen, Laurie J. Goodyear, Frank J. Gonzalez, Bruce M. Spiegelman, C. Ronald Kahn

Research output: Contribution to journalArticlepeer-review

361 Scopus citations

Abstract

Activation of peroxisome proliferator-activated receptor γ (PPARγ) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARγ knockout (MuPPARγKO) using Cre/loxP recombination. Interestingly, MuPPARγKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARγKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARγKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARγKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARγKO mice. Thus, muscle PPARγ is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.

Original languageEnglish
Pages (from-to)608-618
Number of pages11
JournalJournal of Clinical Investigation
Volume112
Issue number4
DOIs
StatePublished - Aug 2003

ASJC Scopus subject areas

  • Medicine (all)

Fingerprint

Dive into the research topics of 'Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones'. Together they form a unique fingerprint.

Cite this