The ancient drug salicylate indirectly targets fructose-1,6-bisphosphatase to suppress liver glucose production in diet-induced obese mice

TY - JOUR

T1 - The ancient drug salicylate indirectly targets fructose-1,6-bisphosphatase to suppress liver glucose production in diet-induced obese mice

AU - Nisr, Raid B.

AU - Atrih, Abdelmadjid

AU - Gutierrez Lara, Erika J.

AU - Lamont, Douglas

AU - Luda, Katarzyna M.

AU - McCrimmon, Rory J.

AU - Sakamoto, Kei

AU - Rena, Graham

AU - McNeilly, Alison D.

N1 - Publisher Copyright: © 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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.

KW - fructose-1,6-bisphosphatase

KW - glucose

KW - liver

KW - obesity

KW - salicylate

UR - https://www.scopus.com/pages/publications/105005980012

U2 - 10.1111/apha.70058

DO - 10.1111/apha.70058

M3 - Article

C2 - 40400417

SN - 1748-1708

VL - 241

JO - Acta Physiologica

JF - Acta Physiologica

IS - 6

M1 - e70058

ER -