Cdkn2a regulates beige fat maintenance through BECN1-mediated autophagy

A potential therapeutic target to curb the obesity and diabetes epidemic is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of Cdkn2a as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and mice are more resistant to diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistic studies demonstrate that Cdkn2a promotes the expression and activity of BECN1 by directly binding to its mRNA and its negative regulator BCL2L1, activating autophagy and accelerating the beige-to-white transition. Notably, reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a-ablation. Furthermore, hyperactive BECN1 alone significantly accelerates the beige-to-white transition. Collectively, these findings show that Cdkn2a-mediated autophagy serves as a brake system for beige adipocyte maintenance and is a highly promising target for anti-obesity and anti-diabetes therapy. HighlightsO_LICdkn2a ablation promotes beige fat maintenance and ameliorates diet-induced obesity C_LIO_LILoss of Cdkn2a retains beige adipocytes by inhibiting BECN1-mediated autophagy C_LIO_LICdkn2a modulates BECN1 by binding to its mRNA and its inhibitor BCL2L1, respectively C_LIO_LIHyperactive BECN1 is sufficient to accelerate the beige-to-white transition C_LI