期刊
DEVELOPMENTAL CELL
卷 5, 期 4, 页码 657-663出版社
CELL PRESS
DOI: 10.1016/S1534-5807(03)00274-0
关键词
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资金
- NIDDK NIH HHS [U24 DK-59635, DK49210, R01 DK040936, R01 DK40936, R01 DK080756, R01 DK49780, P30 DK19525, P01 DK49210] Funding Source: Medline
Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.
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