ALKBH5 activates creatine-driven thermogenesis by stabilizing CKB mRNA in response to cold.

Non-shivering thermogenesis contributes to increased energy expenditure and can be a potential therapy to combat obesity. Here we show that the adipose tissue N6-methyladenosine (m6A) demethylase ALKBH5 responds to cold and adrenergic stimulation to induce non-shivering thermogenesis independent of UCP1. Fat-specific Alkbh5 knockout reduces thermogenic capacity, increases susceptibility to obesity and disrupts glucose homoeostasis in both male and female mice. Conversely, Alkbh5 overexpression in thermogenic fat increases energy expenditure and improves systemic metabolism. Furthermore, fat ALKBH5 expression inversely correlates with obesity in humans. Mechanistically, ALKBH5 is transcriptionally induced by the cAMP/PKA/CREB pathway in response to thermogenic stimuli. ALKBH5 demethylates m6A on CKB mRNA and prevents its degradation mediated by YTHDF2, thereby enhancing creatine metabolism-mediated thermogenesis in both wild-type and Ucp1-knockout mice. These findings suggest that ALKBH5 transduces thermogenic signalling towards creatine-driven thermogenesis, serving as a potential target for the treatment of obesity.