Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules¹. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation^2,3,4,5,6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1–containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1–selective activators and promote LCFA oxidation.

长链脂肪酸（LCFA）在细胞能量代谢中起着重要作用，既是重要的能量来源，又是信号分子¹。LCFA-CoA酯通过充当乙酰辅酶A羧化酶的变构抑制剂来促进自身氧化，从而减少丙二酰辅酶A的生成并减轻对肉碱棕榈酰转移酶1的抑制，从而促进LCFA-CoA转运到线粒体中进行β氧化。^2,3,4,5,6。在这里，我们报道了一个新的法规水平，其中LCFA-CoA酯本身会变构激活含AMP的蛋白激酶（AMPK）β1的同工型，从而通过乙酰CoA羧化酶的磷酸化来增加脂肪酸的氧化。LCFA-CoA酯激活AMPK需要在α-亚基激酶结构域和β-亚基之间形成变构药物和代谢位点。小分子活化剂A769662抑制AMPK活化的β1亚基突变与变构药物和代谢物位点结合，也抑制LCFA-CoAs活化。因此，LCFA-CoA代谢产物可作为直接内源性AMPKβ1选择性激活剂，并促进LCFA氧化。