Essential Role for miR-196a in Brown Adipogenesis of White Fat Progenitor Cells

Abstract

Author SummaryObesity is caused by the accumulation of surplus energy in a fatty tissue called white adipose tissue (WAT) and can lead to important health problems such as diabetes. Mammals additionally possess brown adipose tissue (BAT), which serves to generate body heat to stabilize body temperature under exposure to cold, and is abundant in hibernating animals and human neonates. In performing its function BAT consumes energy, thereby reducing WAT fat accumulation. Recent studies have shown that exposure to a cold environment stimulates the partial conversion of WAT to BAT in mice, and given that human adults have a limited amount of BAT, such a conversion has the potential to afford a novel method of obesity control. Here, we analyze the molecular mechanism of this conversion using genetically manipulated mice and cells isolated from human adipose tissue. We find that the expression levels of a microRNA, miR-196a, positively correlate with the conversion of WAT to BAT under cold exposure conditions. We show that forced expression of miR-196a in mouse adipose tissue increases BAT content and energy expenditure, thereby rendering the animals resistant to obesity and diabetes. Mechanistically, we observe that miR-196a acts by inhibiting the expression of the homeotic gene Hoxc8, a repressor of brown adipogenesis. These findings introduce the therapeutic possibility of using microRNAs to control obesity and its associated diseases in humans.