Division of Gastroenterology & Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Metabolism. 2021 May;118:154731. doi: 10.1016/j.metabol.2021.154731. Epub 2021 Feb 23.
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.
We developed global NTPDase3 deficient (Entpd3) and islet beta-cell-specific NTPDase-3 deficient mice (Entpd3) using Ins1-Cre targeted gene editing to compare metabolic phenotypes with wildtype (WT) mice on a high-fat diet (HFD).
Entpd3 mice exhibited similar growth rates compared to WT on chow diet. 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 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 inguinal white adipose tissue with upregulation of UCP-1 and related genes involved in thermogenesis in Entpd3 mice.
Global NTPDase3 deletion in mice is associated with resistance to DIO and 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.
外核苷酸三磷酸二磷酸水解酶 3（NTPDase3），也称为 CD39L3，是胰岛和神经中β细胞表达的主要外核苷酸酶。NTPDase3 催化细胞外 ATP 和 ADP 转化为 AMP，并调节嘌呤能信号。先前的研究表明，NTPDase3 可减少体外β细胞的胰岛素释放。本研究旨在确定 NTPDase3 在体内饮食诱导肥胖（DIO）和代谢中的作用。
我们使用 Ins1-Cre 靶向基因编辑技术构建了全局 NTPDase3 缺失（Entpd3）和胰岛β细胞特异性 NTPDase-3 缺失（Entpd3）小鼠，以比较高脂肪饮食（HFD）下的代谢表型与野生型（WT）小鼠。
Entpd3 小鼠在正常饮食下的生长速度与 WT 相似。当喂食 HFD 时，Entpd3 小鼠对 DIO 表现出明显的抗性。Entpd3 小鼠每天消耗更多的卡路里，粪便热量损失更少。尽管 Entpd3 小鼠的运动活性没有增加，但它们在 HFD 下的基础代谢率显著增加。这种有益的表型与改善的葡萄糖耐量有关，但与更高的胰岛素分泌无关。事实上，Entpd3 小鼠与匹配的对照组相比表现出相似的代谢表型和胰岛素分泌，表明β细胞中 NTPDase3 的表达不是主要的保护因素。相反，我们观察到棕色脂肪组织中解偶联蛋白 1（UCP-1）的表达增加，腹股沟白色脂肪组织中的脂肪褐变增强，UCP-1 及其相关基因的表达上调，与产热有关。
在小鼠中，全局 NTPDase3 缺失与 DIO 和肥胖相关的葡萄糖耐量降低有关。这种结果不是由胰岛β细胞中 NTPDase3 的表达驱动的，而是可能通过脂肪细胞的代谢变化介导的。
