Journal article
Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones
The Journal of clinical investigation, Vol.112(4), pp.608-618
08/15/2003
DOI: 10.1172/JCI17305
PMCID: PMC171387
PMID: 12925701
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.
Details
- Title: Subtitle
- Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones
- Creators
- Andrew W. Norris - Harvard UniversityLihong Chen - Harvard UniversitySimon J. Fisher - Harvard UniversityIldiko Szanto - Harvard UniversityMichael Ristow - Harvard UniversityAlison C. Jozsi - Harvard UniversityMichael F. Hirshman - Harvard UniversityEvan D. Rosen - Harvard UniversityLaurie J. Goodyear - Harvard UniversityFrank J. Gonzalez - National Institutes of HealthBruce M. Spiegelman - Harvard UniversityC. Ronald Kahn - Harvard University
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.112(4), pp.608-618
- DOI
- 10.1172/JCI17305
- PMID
- 12925701
- PMCID
- PMC171387
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 08/15/2003
- Academic Unit
- Endocrinology and Diabetes; Stead Family Department of Pediatrics; Biochemistry and Molecular Biology
- Record Identifier
- 9984293078302771
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