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

TitleMacrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.
Publication TypeJournal Article
Year of Publication2007
AuthorsHevener AL, Olefsky JM, Reichart D, Nguyen AMT, Bandyopadyhay G, Leung H-Y, Watt MJ, Benner C, Febbraio MA, Nguyen A-K, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M
JournalJ Clin Invest
Volume117
Issue6
Pagination1658-69
Date Published2007 Jun
ISSN0021-9738
KeywordsAdipocytes, Animals, Base Sequence, DNA Primers, Gene Expression Profiling, Hypoglycemic Agents, Insulin Resistance, Liver, Macrophages, Mice, Mice, Knockout, Mice, Transgenic, Muscle, Skeletal, PPAR gamma, Promoter Regions, Genetic, Thiazolidinediones
Abstract

PPAR gamma 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 PPAR gamma 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. PPAR gamma-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 PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.

DOI10.1172/JCI31561
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/17525798?dopt=Abstract
PMCPMC1868788
Alternate TitleJ. Clin. Invest.
PubMed ID17525798