Global deletion of NTPDase3 protects against diet-induced obesity by increasing basal energy metabolism

Background: Ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), also known as CD39L3, is the dominant ectonucleotidase expressed by beta cells in the islet of Langerhans and on nerves. NTPDase3 catalyzes the conversion of extracellular ATP and ADP to AMP and modulates purinergic signaling. Previous studies have shown that NTPDase3 decreases insulin release from beta-cells in vitro. This study aims to determine the impact of NTPDase3 in diet-induced obesity (DIO) and metabolism in vivo. Methods: We developed global NTPDase3 deficient (Entpd3(-/-)) and islet beta-cell-specific NTPDase-3 deficient mice (Entpd3(flox/flox,Ins-Cre)) using Ins1-Cre targeted gene editing to compare metabolic phenotypes with wildtype (WT) mice on a high-fat diet (HFD). Results: Entpd3(-/-) mice exhibited similar growth rates compared toWT on chowdiet. When fed HFD, Entpd3(-/-)mice demonstrated significant resistance to DIO. Entpd3(-/-) mice consumed more calories daily and exhibited less fecal calorie loss. Although Entpd3(-/-) mice had no increases in locomotor activity, the mice exhibited a significant increase in basal metabolic rate when on the HFD. This beneficial phenotype was associated with improved glucose tolerance, but not higher insulin secretion. In fact, Entpd3(flox/flox,InsCre) mice demonstrated similar metabolic phenotypes and insulin secretion compared to matched controls, suggesting that the expression of NTPDase3 in beta-cells was not the primary protective factor. Instead, we observed a higher expression of uncoupling protein 1 (UCP-1) in brown adipose tissue and an augmented browning in inguinalwhite adipose tissue with upregulation of UCP-1 and related genes involved in thermogenesis in Entpd3(-/-) mice. Conclusions: Global NTPDase3 deletion in mice is associated with resistance to DIOand obesity-associated glucose intolerance. This outcome is not driven by the expression of NTPDase3 in pancreatic beta-cells, but rather likely mediated through metabolic changes in adipocytes. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study investigated the impact of NTPDase3 deficiency on diet-induced obesity and metabolism in mice. The results showed that global NTPDase3 deletion led to resistance to obesity and glucose intolerance, with metabolic changes in adipocytes playing a key role rather than NTPDase3 expression in pancreatic beta-cells.