Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
Andrea L. Hevener, … , Christopher K. Glass, Mercedes Ricote
Andrea L. Hevener, … , Christopher K. Glass, Mercedes Ricote
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1658-1669. https://doi.org/10.1172/JCI31561.
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Research Article Metabolism

Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

Abstract

PPARγ is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPARγ in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPARγ-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPARγ following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPARγ in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.

Authors

Andrea L. Hevener, Jerrold M. Olefsky, Donna Reichart, M.T. Audrey Nguyen, Gautam Bandyopadyhay, Ho-Yin Leung, Matthew J. Watt, Chris Benner, Mark A. Febbraio, Anh-Khoi Nguyen, Brian Folian, Shankar Subramaniam, Frank J. Gonzalez, Christopher K. Glass, Mercedes Ricote

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Figure 5

Loss of PPARγ causes macrophage activation and secretion of insulin resistance producing molecules.

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Loss of PPARγ causes macrophage activation and secretion of insulin resi...
Altered expression of ABCG1 (A), MCP-1 (B), Cxcl14 (C), and retnla (D) in TG-Mφ from NC-fed BMT MAC-KO (n = 9; black bars) versus BMT MAC-WT (n = 9; white bars) mice. (E) TG-Mφ showing advanced stress fiber formation in the BMT MAC-KOs (NC-fed). Impaired insulin-stimulated 2-deoxyglucose uptake into L6 myocytes incubated with CM from vehicle- (Veh-) or FFA-treated TG-Mφ harvested from BMT MAC-KO (n = 6) versus BMT MAC-WT (n = 6) mice (F and G) and increased GFP-labeled BM-derived cells in skeletal muscle from mice fed a HFD (black bar) versus NC (white bar) (H). Values for RT-PCR are expressed as mean ± SEM. *P < 0.05 between genotypes. Insulin-stimulated 2-DOG assays represent 6 wells per condition and are expressed as mean ± SEM in cpm/μg of protein for absolute tracer uptake values (F) and uptake expressed above basal (G). *P < 0.05, BMT MAC-WT versus BMT MAC-KO, within incubation condition; †P < 0.05, vehicle versus FFA, within genotype. (H) GFP immunoblots were quantified using densitometric analysis, and mean expression values ± SEM are presented. n = 4 per group. **P < 0.05 between dietary groups. (I) Immunohistochemical detection shows increased CD11c- and F4/80-expressing cells in skeletal muscle following 8 weeks of high-fat feeding.