Zeng Xinliu, Wang Yongjie, Farias Karina, Rappa Andrew, Darko Christine, Sauve Anthony, Huang Qingxia, Alonso Laura C, Yang Yue
Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, United States of America; Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, United States of America; Department of Animal Sciences, North Carolina A&T State University, Greensboro, NC 27411, United States of America.
Metabolism. 2025 Mar;164:156110. doi: 10.1016/j.metabol.2024.156110. Epub 2024 Dec 20.
NAD deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD synthesis.
Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.
NRH entered tissues unassisted and was rapidly metabolized for NAD biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.
This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD enhancement.
NAD缺乏是肥胖诱导的代谢紊乱的基础。本研究评估了强效NAD增强剂二氢烟酰胺核糖苷（NRH）在瘦小鼠和肥胖小鼠中的作用，并探讨NRH是否通过一种涉及腺苷激酶（ADK）的独特机制发挥作用，ADK是一种对NRH驱动的NAD合成至关重要的酶。
在健康小鼠腹腔内单次注射250mg/kg NRH后进行药代动力学和药效学分析。在长期研究中，给瘦小鼠和高脂饮食诱导的肥胖小鼠每周三次注射250mg/kg NRH，持续7周。监测血液NAD水平、身体组成、能量消耗以及葡萄糖和脂质代谢。为了测试ADK的作用，在肥胖小鼠中将ADK抑制剂ABT702与NRH联合给药。
NRH无需辅助即可进入组织，并迅速代谢用于NAD生物合成，而ADK抑制则阻断其磷酸化，导致NRH在所有检测组织中积累，并可能释放回循环中。7周的NRH给药在瘦小鼠和肥胖小鼠中均耐受性良好。在肥胖小鼠中，NRH通过促进胰岛素分泌、增强肌肉胰岛素信号传导和减少肝糖异生来改善葡萄糖稳态。它还降低了脂肪量，降低了血脂，并改善了白色脂肪功能。这些益处与组织NAD水平升高、Sirtuin活性增强和线粒体抗氧化防御增加有关。ADK抑制消除了这些作用，证实NRH直接进入组织并随后磷酸化对其全部益处至关重要。
本研究确定NRH是一种有前途的治疗肥胖诱导的代谢功能障碍的药物，通过ADK依赖的NAD增强来纠正葡萄糖不耐受和高脂血症。
