The ancient drug salicylate indirectly targets fructose‐1,6‐bisphosphatase to suppress liver glucose production in diet‐Induced obese mice
Author(s)
Type
Journal Article
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.
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.
Date Issued
2025-06-01
Date Acceptance
2025-05-05
Citation
Acta Physiologica, 2025, 241 (6)
ISSN
1748-1708
Publisher
Wiley
Journal / Book Title
Acta Physiologica
Volume
241
Issue
6
Copyright Statement
© 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40400417
Subjects
fructose‐1,6‐bisphosphatase
glucose
liver
obesity
salicylate
Animals
Fructose-Bisphosphatase
Salicylates
Liver
Mice
Obesity
Glucose
Gluconeogenesis
Male
Mice, Obese
Mice, Inbred C57BL
Diet, High-Fat
Publication Status
Published
Coverage Spatial
England
Article Number
e70058
Date Publish Online
2025-05-22