Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

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-oxidation2–6. 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. Steinberg and colleagues show that long-chain fatty acyl-CoA esters are endogenous ligands for the drug-binding domain of AMPK β1–containing isoforms, and that such binding is critical for enhancement of fatty acid oxidation. These data may help explain how AMPK integrates responses to ketogenic diets, fasting or endurance exercise across distinct tissues in the absence of changes in adenine nucleotides.