Abstract

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.