Analysis of a novel metabolic syndrome model mouse and its molecular mechanism

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A mutant mouse defective in sequestosome1 gene causes mature-onset obesity. A previous study suggested importance of sequestosome1 (SQSTM1/p62) in regulation of adipocyte differentiation as a cause of obesity formation. However, our studies show overeating is the cause of the obesity formation. We constructed brain-specific SQSTM1 knock-down mouse. We found the conditional knock-down mouse exhibited similar body weight increase as the whole body gene knock-out mouse. We showed SQSTM1 is highly expressed in neurons of hypothalamus, suggesting a possibility that SQSTM1 is involved in the intracellular signaling of anorexic hormone leptin. Interesting finding is a female hormone estradiol compensates the lack of SQSTM1 in body weight control. It inhibits obesity formation through suppression of overeating of the mutant mice.