Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Genetics & Heredity, Medicine, Research & Experimental, Research & Experimental Medicine, Soluble 5 '-nucleotidase II, CN-II, NT5C2, High-fat diet, Glucose metabolism, Type 2 diabetes, Fat mass, AMPK, ACTIVATED PROTEIN-KINASE, NUCLEOTIDE LEVELS, AMPK ACTIVATION, URIC-ACID, DEAMINASE, INHIBITION, MECHANISMS, ENERGY, Soluble 5′-nucleotidase II, 5'-Nucleotidase, Animals, Diet, High-Fat, Gene Deletion, Glucose, Insulin Resistance, Lipolysis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Obesity, Weight Gain, 1103 Clinical Sciences, 3105 Genetics, 3202 Clinical sciences

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.