The Ancient Drug Salicylate Indirectly Targets Fructose‐1,6‐Bisphosphatase to Suppress Liver Glucose Production in Diet‐Induced Obese Mice

ABSTRACT Aims The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti‐hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5′‐adenosine monophosphate ( AMP )‐dependent inhibition of fructose‐1,6‐bisphosphatase 1 ( FBP1 ) to the anti‐hyperglycaemic action of salicylate. Methods We studied AMP ‐insensitive FBP1 G27P knockin ( KI ) mice through a variety of cellular approaches, including proteomics, Seahorse metabolic analysis, glucose production, and other assays, in addition to a detailed assessment of metabolic responses in vivo. Results Compared with wild‐type littermates, AMP ‐insensitive FBP1 KI mice were resistant to the effects of the drug on body weight, glucose tolerance, pyruvate disposal, liver lipid content and hepatic glucose production. Compared with wild‐type, KI hepatocytes exhibited baseline differences in glycolytic, TCA cycle and fatty acid oxidation enzyme levels, potentially linking gluconeogenic dysregulation and its reversal to non‐carbohydrate fuel management. Conclusion Collectively, our data highlight a novel mechanism of action for the effects of salicylate on glycaemia and weight gain, which depends on AMP‐mediated allosteric inhibition of FBP1.