Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones
Andrew W. Norris, … , Bruce M. Spiegelman, C. Ronald Kahn
Andrew W. Norris, … , Bruce M. Spiegelman, C. Ronald Kahn
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):608-618. https://doi.org/10.1172/JCI17305.
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Article Metabolism

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

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.

Authors

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

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Figure 1

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Recombination of PPARγ-loxP allele in the muscle of MuPPARγKO mice. (a) ...
Recombination of PPARγ-loxP allele in the muscle of MuPPARγKO mice. (a) Schematic of recombinant mouse PPARγ alleles indicating PCR primers sets, BamHI restriction sites (labeled as B), loxP sites (open triangles), and Probe 1 for Southern blot analysis. (b) Detection of intact (fl) versus recombined (null) allele by PCR on genomic DNA from muscle (M) or liver (L). The fl and null alleles appear at approximately 2 kb and 400 bp, respectively. (c) Southern blot analysis of BamHI-digested genomic DNA isolated from muscle samples from Lox and MuPPARγKO (KO) mice. Hybridization was performed with Probe 1, identifying fragments of 10 and 8 kb for fl and null alleles, respectively. (d) PCR detection of unrecombined alleles (primer sets A and B) or any WT, fl, or null allele (primer set C) in genomic DNA isolated from enriched myocytes of WT, Lox, and KO mice. Primer sets A and B yield larger products in the fl compared with WT allele due to loxP insertion.