Publication in detail

Diabetes 2010 Apr;59(4):883-93. Epub 2010 Jan

Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.

Chan, CB; Jun, JY; Jung, DY; Kim, JK; Liu, X; Luo, HR; Ye, K.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

>OBJECTIVE: Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in obesity development. RESEARCH DESIGN AND METHODS: Whole-body PIKE knockout mice were generated and subjected to high-fat-diet feeding for 20 weeks. The glucose tolerance, tissue-specific insulin sensitivity, adipocyte differentiation, and lipid oxidation status were determined. The molecular mechanism of PIKE in the insulin signaling pathway was also studied. RESULTS: We show that PIKE-A regulates obesity development by modulating AMP-activated protein kinase (AMPK) phosphorylation. PIKE-A is important for insulin to suppress AMPK phosphorylation. The expression of PIKE-A is markedly increased in adipose tissue of obese mice, whereas depletion of PIKE-A inhibits adipocyte differentiation. PIKE knockout mice exhibit a prominent phenotype of lipoatrophy and are resistant to high-fat diet-induced obesity, liver steatosis, and diabetes. PIKE knockout mice also have augmented lipid oxidation, which is accompanied by enhanced AMPK phosphorylation in both muscle and adipose tissue. Moreover, insulin sensitivity is improved in PIKE-A-deficient muscle and fat, thus protecting the animals from diet-induced diabetes. CONCLUSIONS: Our results suggest that PIKE-A is implicated in obesity and associated diabetes development by negatively regulating AMPK activity.

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