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.

Integrated Analysis of Summary Statistics to Identify Pleiotropic Genes and Pathways for the Comorbidity of Schizophrenia and Cardiometabolic Disease

“…NT5C2 encodes a cytosolic purine 5′-nucleotidase (cytosolic 5′-nucleotidase II) involved in cellular purine metabolism (53), which is associated with SCZ, BMI, and CAD. Previous studies have shown that loss of function of NT5C2 gene reduced body weight gain, improved glucose tolerance, reduced plasma insulin and triglyceride in high-fat diet mice (54). However, a recent study showed that knockdown of neuronal CG32549 in D. melanogaster, which is similar to NT5C2 protein in human, is associated with impaired motility behavior (55).…”

Cytosolic 5′-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator

“…Some of the effects exerted by these modifications are cell-specific, but there are several interesting consequences in common among the utilized cell models. The intracellular purine and pyrimidine nucleotides are increased or unaffected by silencing, while they are decreased in overexpressing cells [8][9][10][11][12][13][14][15][16]. Similar effects were observed in cells expressing mutant forms of NT5C2 [17,18].…”

Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

“…Our results on tumoral cell models in which cN-II was partially silenced demonstrated that low activity correlates with a more oxidative phenotype, with low rate of protein synthesis, high mitochondrial content, high antioxidant defense, with a concomitant activation of p53, but the causal relationship was not demonstrated [8]. Furthermore, in a mice model, the knockout of the enzyme was associated with reduced body weight also after a high-fat diet [17]. Consistently, a single-nucleotide polymorphism in NT5C2 (the cN-II gene) was associated with a lower tendency to accumulate adipose tissue in Japanese women [18,19].…”