Deleting Bmp4 in brown fat unlocks an arachidonic acid-AMPK axis to boost energy expenditure

Fasting enhances lipolysis in white adipose tissue (WAT), releasing fatty acids (FAs) which are subsequently metabolized through β-oxidation in the liver and brown adipose tissue (BAT). Although BAT is a key site for FA utilization, the specific FAs taken up and oxidized during fasting-as well as their systemic metabolic effects-remain poorly defined. Time-course analysis revealed that fasting reprograms BAT to promote the esterification and storage of circulating FAs rather than their immediate oxidation. This lipid pool was selectively enriched in long-chain polyunsaturated fatty acids (LCPUFAs), particularly arachidonic acid (AA). Genetic (BAT-specific knockout of bone morphogenetic protein 4, Bmp4) or pharmacological (Inhibition of diacylglycerol acyltransferase, DGAT) disruption of this FA esterification process potently enhanced mitochondrial function and systemic energy expenditure. Mechanistically, AA activated AMP-activated protein kinase (AMPK), thereby enhancing energy expenditure through increased mitochondrial biogenesis. Our work reveals a fasting-inducible, AA-centric signaling pathway that senses lipid storage status. Through activation of AMPK, it couples suppressed FA esterification to enhanced oxidation, positioning BMP4 as a critical regulator of this metabolic switch.