Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.

棕色脂肪组织 （BAT） 参与徒劳的脂肪酸合成-氧化循环，其目的仍然难以捉摸。在这里，我们表明 ATP-柠檬酸裂解酶 （ACLY） 产生乙酰辅酶 A 用于脂肪酸合成，通过减轻代谢应激来促进产热。如果没有 ACLY，BAT 会使三羧酸循环过载，激活综合应激反应 （ISR） 并抑制产热。当小鼠断奶摄入碳水化合物丰富的饮食时，ACLY 在防止 BAT 应激方面的作用变得至关重要，而去除膳食碳水化合物可以防止 ACLY 缺陷型 BAT 的应激诱导。ACLY 缺失也上调脂肪酸合酶 （Fasn）;然而，虽然 ISR 激活本身不是由脂肪酸合成受损引起的，但删除 Fasn 和 Acly 可解锁另一种代谢程序，克服三羧酸循环过载，防止 ISR 激活并挽救产热。总体而言，我们揭示了 ACLY 在减轻线粒体应激方面以前未被重视的作用，该作用将膳食碳水化合物与解偶联蛋白 1 依赖性产热联系起来，并为 BAT 中的脂肪酸合成-氧化悖论提供了基本见解。