Genetic deletion of soluble 5'-nucleotidase II reduces body weight gain and insulin resistance induced by a high-fat diet.

Abstract

We previously investigated whether inhibition of AMP-metabolizing enzymes could enhance AMP-activated protein kinase (AMPK) activation in skeletal muscle for the treatment of type 2 diabetes. Soluble 5'-nucleotidase II (NT5C2) hydrolyzes IMP and its inhibition could potentially lead to a rise in AMP to activate AMPK. In the present study, we investigated effects of NT5C2 deletion in mice fed a normal-chow diet (NCD) or a high-fat diet (HFD). On a NCD, NT5C2 deletion did not result in any striking metabolic phenotype. On a HFD however, NT5C2 knockout (NT5C2-/-) mice displayed reduced body/fat weight gain, improved glucose tolerance, reduced plasma insulin, triglyceride and uric acid levels compared with wild-type (WT) mice. There was a tendency towards smaller and fewer adipocytes in epididymal fat from NT5C2-/- mice compared to WT mice, consistent with a reduction in triglyceride content. Differences in fat mass under HFD could not be explained by changes in mRNA expression profiles of epididymal fat from WT versus NT5C2-/- mice. However, rates of lipolysis tended to increase in epididymal fat pads from NT5C2-/- versus WT mice, which might explain reduced fat mass. In incubated skeletal muscles, insulin-stimulated glucose uptake and associated signalling were enhanced in NT5C2-/- versus WT mice on HFD, which might contribute towards improved glycemic control. In summary, NT5C2 deletion in mice protects against HFD-induced weight gain, adiposity, insulin resistance and associated hyperglycemia.

• Authors: Manuel Johanns, Samanta Kviklyte, Sheng-Ju Chuang, Katrien Corbeels, Roxane Jacobs, Gaëtan Herinckx, Didier Vertommen, Olivier Schakman, Thibaut Duparc, Patrice D Cani, Caroline Bouzin, Harriet Andersén, Mohammad Bohlooly-Y, Bart Van der Schueren, Jan Oscarsson, Mark H Rider
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 126 Issue 4 Pg. 377-387 (04 2019) ISSN: 1096-7206 [Electronic] United States
• PMID: 30803894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 5'-Nucleotidase
• NT5C2 protein, mouse
• Glucose

Topics

• 5'-Nucleotidase (genetics)
• Animals
• Diet, High-Fat (adverse effects)
• Gene Deletion
• Glucose (metabolism)
• Insulin Resistance
• Lipolysis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Skeletal (metabolism)
• Obesity (genetics, prevention & control)
• Weight Gain