Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) activation enhances insulin sensitivity in type 2 diabetes mellitus. However, downstream mediators of PPARγ activation in adipocytes and myotubes, the most important cell types involved in glucose homeostasis, remained unclear. Here we show by using two synthetic PPARγ agonists (rosiglitazone and KR-62776, a novel PPARγ agonist) that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a key downstream mediator of PPARγ signaling. The PPARγ agonists down-regulated PTEN expression, resulting in glucose uptake increase in differentiated 3T3-L1 adipocytes and C2C12 skeletal muscle cells. In both cells, PTEN knockdown increased glucose uptake, whereas overexpression abolished the agonist-induced effects. The effects of PPARγ agonists on PTEN expression and glucose uptake disappeared by pretreatment with a PPARγ antagonist or by knockdown of PPARγ expression. In vivo treatment of the agonists to C57BL/6J-ob/ob mice resulted in the reduction of PTEN level in both adipose and skeletal muscle tissues and decreased plasma glucose levels. Thus, these results suggest that PTEN suppression is a key mechanism of the PPARγ-mediated glucose uptake stimulation in insulin-sensitive cells such as adipocytes and skeletal muscle cells, thereby restoring glucose homeostasis in type 2 diabetes.
Footnotes
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This research was supported by grant from the Center for Biological Modulators of the 21st Century Frontier R&D Program, The Ministry of Science and Technology, Korea.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.031948.
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; BADGE, bisphenol A diglycidyl ether; PTEN, phosphatase and tensin homolog deleted on chromosome 10; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ATCC, American Type Culture Collection; KRP, Krebs-Ringer phosphate; PCR, polymerase chain reaction; ob/ob mice, C57BL/6J-ob/ob mice; GW9662, 2-chloro-5-nitrobenzanilide; PI-3, phosphoinositide-3.
- Received October 19, 2006.
- Accepted March 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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