Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity.
Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity.
复制标题
DOI：
10.1016/j.celrep.2018.09.034
复制
发表时间：
2018-10-09
期刊：
影响因子：
8.8
通讯作者：
Brüning JC
中科院分区：
文献类型：
--
作者：
Timper K;Paeger L;Sánchez-Lasheras C;Varela L;Jais A;Nolte H;Vogt MC;Hausen AC;Heilinger C;Evers N;Pospisilik JA;Penninger JM;Taylor EB;Horvath TL;Kloppenburg P;Brüning JC
线粒体氧化磷酸化（OXPHOS）和底物利用关键调节下丘脑阿黑皮素原（POMC）表达神经元的功能。在这里，我们证明了POMC神经元中的凋亡诱导因子（AIF）的失活轻度损害线粒体呼吸，并减少瘦小鼠POMC神经元的放电。相比之下，在饮食诱导的肥胖条件下，AIF的POMC-Cre特异性失活防止肥胖诱导的POMC神经元沉默，转化为改善的葡萄糖代谢，改善的瘦素和胰岛素敏感性，以及AIFΔPOMC小鼠中增加的能量消耗。在细胞水平上，AIF缺乏改善线粒体形态，促进脂肪酸用于线粒体呼吸，并增加来自肥胖小鼠的POMC神经元中的活性氧（ROS）形成，最终导致HFD喂养后恢复的POMC放电。总的来说，线粒体功能的部分损伤将POMC神经元的底物利用从葡萄糖转移到脂肪酸代谢，并恢复其放电特性，从而改善肥胖症患者的全身葡萄糖和能量代谢。Timper等人表明，在表达下丘脑POMC的神经元中缺失AIF或MPC 1后，线粒体OXPHOS的轻度损伤增加了它们的脂肪酸利用和ROS形成，防止了肥胖诱导的这些神经元的沉默，并改善了肥胖症中的全身葡萄糖代谢。
Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity. Timper et al. show that mild impairment of mitochondrial OXPHOS upon deletion of AIF or MPC1 in hypothalamic POMC-expressing neurons increases their fatty acid utilization and ROS formation, prevents obesity-induced silencing of these neurons, and improves systemic glucose metabolism in obesity.
登录
查看更多内容
影响因子：
16.2
作者：
Dhillon, H;Zigman, JM;Lowelll, BB
通讯作者：
Lowelll, BB
影响因子：
3.8
作者：
Horn, R;Marty, A
通讯作者：
Marty, A
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
4.1
作者：
FERRE, P;LETURQUE, A;GIRARD, J
通讯作者：
GIRARD, J
影响因子：
15.9
作者：
Berglund, Eric D.;Vianna, Claudia R.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.