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Title: TRANSGENIC EXPRESSION OF MYOSTATIN PROPEPTIDE PREVENTS DIET-INDUCED OBESITY AND INSULIN RESISTANCE

Author
item ZHAO, BAOPING - UNIVERSITY OF HAWAII
item Wall, Robert
item YANG, JINZENG - UNIVERSITY OF HAWAII

Submitted to: Journal of Biochemical and Biophysical Methods
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/15/2005
Publication Date: 11/11/2005
Citation: Zhao, B., Wall, R.J., Yang, J. 2005. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochemical and Biophysical Research Communications. 337(1):248-255.

Interpretive Summary: To study growth and development, we created a line of mice, in which the function of myostatin was compromised. The resulting transgenic mice had 40% increased muscle mass and 25% less body fat compared to their littermates controls. In this study we asked whether the increased muscularity could ameliorate the consequences of high fat diets on development of obesity and diabetes. After feeding a high fat diet for two months control mice became obese but the transgenic mice did not. Furthermore, while the controls became insulin resistance and had impaired glucose tolerance the transgenic mice remained healthy. We suspected the differences had to be controlled by hormone interactions between skeletal muscle and adipose tissue. Concentrations of insulin, leptin and resistin were normal in transgenic mice fed normal or high-fat diets, but were elevated over 100% in high-fat diet control mice. Akt, an intermediate in the insulin signaling pathway was evaluated in high-fat diet transgenics compared to controls. Insulin resistance is associated with impaired Akt phosphorylation. Our findings demonstrate a hormonal rationale linking the inverse relationship between muscularity and obesity and suggest that the myostatin prodomain peptide might have potential as a useful therapeutic in treating obesity.

Technical Abstract: High-fat diet induces obesity and insulin resistance. To study effects of enhanced muscles on obesity prevention, we generated transgenic mice through muscle-specific expression of the prodomain (the 5’-region 886 nucleotides) of myostatin, a key gene that plays a negative role in controlling muscle mass. Transgenic mice showed dramatic growth and muscling by nine weeks of age. After two-month challenge by 45% high-fat diet, wild-type mice had excessive adipose tissue mass, and developed insulin resistance and impaired glucose tolerance while transgenic mice were healthy, and had normal fat mass. Insulin signaling, measured by Akt phosphorylations, was significantly elevated by 144% in transgenic mice over wild-type mice fed a high-fat diet. Interestingly, high-fat diet induced transgenic mice to increase adiponectin secretion, but not insulin, resistin, or leptin secretions. Disruption of myostatin function by its prodomain favors dietary fat utilization for skeletal muscles, suggesting importance of muscle-fat interactions in obesity prevention.