Cdkn2aregulates beige fat maintenance through BECN1-mediated autophagy

SUMMARYA 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 ofCdkn2aas a molecular pedal for the beige-to-white transition. Beige adipocytes lackingCdkn2aexhibit prolonged lifespan, and mice are more resistant to diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistic studies demonstrate thatCdkn2apromotes 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 byCdkn2a-ablation. Furthermore, hyperactive BECN1 alone significantly accelerates the beige-to-white transition. Collectively, these findings show thatCdkn2a-mediated autophagy serves as a brake system for beige adipocyte maintenance and is a highly promising target for anti-obesity and anti-diabetes therapy.HighlightsCdkn2aablation promotes beige fat maintenance and ameliorates diet-induced obesityLoss ofCdkn2aretains beige adipocytes by inhibiting BECN1-mediated autophagyCdkn2amodulates BECN1 by binding to its mRNA and its inhibitor BCL2L1, respectivelyHyperactive BECN1 is sufficient to accelerate the beige-to-white transition