Dannawi Maya, Riachi Mansour E, Haddad Antony F, El Massry Mohamed, Haddad Mary, Moukarzel Pamela, Harb Frédéric, Ghadieh Hilda E, Eid Assaad A
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.
AUB Diabetes, American University of Beirut, Faculty of Medicine, Medical Center, Lebanon.
Metabol Open. 2022 Mar 13;14:100175. doi: 10.1016/j.metop.2022.100175. eCollection 2022 Jun.
Peripheral neuropathy (PN) is correlated with obesity and metabolic syndrome. Intermittent fasting (IF) has been described as the cornerstone in the management of obesity; however, its role in prediabetic complications is not well elucidated. Cytochromes P450 Monooxygenases (CYP450) are major sources of Reactive Oxygen Species (ROS) that orchestrate the onset and development of diabetic complications. One of the CYP-metabolites, Expoxyecosatetraenoic Acids (EETs), are considered to be negative regulators of ROS production. In this study, we elucidated the role of IF on ROS production and investigated its influence on prediabetes-induced PN.
C57/BL6 control mice, prediabetic, prediabetic that underwent alternate day fasting with different diet composition, and prediabetic mice treated with EET-metabolizing sEH-inhibitor, AUDA. Body mass composition, metabolic, behavioral, and molecular tests were performed.
High-fat diet (HFD) led to an increase in NADPH-induced ROS production; that was due to an alteration in the epoxygenase pathway assessed by the decrease in CYP1a1/1a2 expression. IF reinstated the homeostatic levels of EETs in HFD-fed mice. Moreover, treatment with AUDA mimicked the beneficial effect observed with IF.
IF and EETs bioavailability have a protective role in prediabetes-induced PN, suggesting a novel interventional strategy in the management of prediabetes and its associated complications.
周围神经病变（PN）与肥胖和代谢综合征相关。间歇性禁食（IF）被认为是肥胖管理的基石；然而，其在糖尿病前期并发症中的作用尚未得到充分阐明。细胞色素P450单加氧酶（CYP450）是活性氧（ROS）的主要来源，ROS在糖尿病并发症的发生和发展中起关键作用。CYP代谢产物之一，环氧二十碳四烯酸（EETs），被认为是ROS产生的负调节因子。在本研究中，我们阐明了IF对ROS产生的作用，并研究了其对糖尿病前期诱导的PN的影响。
C57/BL6对照小鼠、糖尿病前期小鼠、采用不同饮食组成隔日禁食的糖尿病前期小鼠，以及用EET代谢的可溶性环氧化物水解酶（sEH）抑制剂AUDA治疗的糖尿病前期小鼠。进行了身体成分、代谢、行为和分子测试。
高脂饮食（HFD）导致NADPH诱导的ROS产生增加；这是由于通过CYP1a1/1a2表达降低评估的环氧合酶途径改变所致。IF恢复了高脂饮食喂养小鼠中EETs的稳态水平。此外，用AUDA治疗模拟了IF观察到的有益效果。
IF和EETs的生物利用度在糖尿病前期诱导的PN中具有保护作用，提示在糖尿病前期及其相关并发症的管理中一种新的干预策略。
