Role of peroxisome proliferation in leptin resistance

过氧化物酶体增殖在瘦素抵抗中的作用

基本信息

批准号：
10320591
负责人：
Sabrina Diano
金额：
$ 33.75万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320591
关键词：
Role peroxisome proliferation leptin resistance

项目摘要

Previous data from our and others' laboratories (Andrews et al., 2008; Benani et al., 2007; Anderson et al., 2009; Jaillard et al., 2009; Campanucci et al., 2010; Diano et al., 2011; Dietrich et al., 2013; Long et al., 2014) showed that reactive oxygen species (ROS) generation is not merely a by-product of substrate oxidation, but it plays a crucial role in modulating cellular responses involved in the regulation of energy metabolism. We have observed that suppression of ROS levels diminish pro-opiomelanocortin (POMC) cell activation and promote the activity of neuropeptide Y- (NPY)/ agouti related peptide- (AgRP) neurons and feeding, whereas ROS activates POMC neurons and reduces feeding. Mitochondria are primary organelles in the generation of ROS and mitochondrial dynamics, i.e. fission and fusion, alters the production of mitochondrial ROS, with mitochondrial fission decreasing and mitochondrial fusion increasing ROS production. Furthermore, uncoupling protein 2 (UCP2), a mitochondrial protein inducing proton leak and highly expressed in the arcuate nucleus, reduces ROS production. Our published (Coppola et al., 2007; Andrews et al., 2008; Diano et al., 2011; Dietrich et al., 2013; Long et al., 2014) and preliminary data generated during this funding period showed that mitochondrial size in AgRP and POMC neurons changes according to the metabolic state of the organism: while during negative energy balance, characterized by increased AgRP and decreased POMC neuronal activities, mitochondrial size decreases (fission), during positive energy balance (fed state) mitochondrial size increases in AgRP and POMC (fusion). Thus, we hypothesize that the activity levels of POMC and NPY/AgRP neurons require UCP2-mediated mitochondrial dynamics. UCP2-induced mitochondrial fission, by decreasing ROS production, inhibits POMC neurons while activates NPY/AgRP neurons. Furthermore, we hypothesize that fuel availability drives mitochondrial dynamics a more specifically low glucose levels drives fission, while high glucose availability drives fusion. To test our hypothesis that fuel regulation of UCP2-mediated mitochondrial dynamics is an important component in the central regulation of metabolism, 3 Aims are proposed: Aim 1 will test the hypothesis that UCP2-mediated mitochondrial fission inactivates POMC neurons. Aim 2 will test the hypothesis that UCP2-mediated mitochondrial fission activates NPY/AgRP neurons. Aim 3 will test the hypothesis that fuel availability drives mitochondrial dynamics in AgRP and POMC neurons. Specifically we hypothesize that low glucose and high fatty acid environment (negative energy balance) drives fission, while high glucose availability drives fusion. The execution of these studies will deliver novel insights into central regulation of whole body glucose metabolism and offer novel avenues to combat diabetes by targeting brain mitochondrial dynamics.

我们和其他实验室的先前数据（Andrews等，2008； Benani等，2007； Anderson等，Anderson等。 2009; Jaillard等人，2009年； Campanucci等，2010； Diano等，2011； Dietrich等人，2013年； Long等人， 2014年）表明，活性氧（ROS）的产生不仅是底物的副产品氧化，但它在调节能量调节的细胞反应中起着至关重要的作用代谢。我们已经观察到ROS水平的抑制降低了促蛋白酶素（POMC）细胞激活和促进神经肽Y-（NPY）/ Agouti相关肽（AGRP）神经元的活性和进食，而ROS激活POMC神经元并减少喂养。线粒体是主要细胞器在ROS和线粒体动力学的产生中，即裂变和融合，改变了生产线粒体ROS，线粒体裂变降低，线粒体融合增加ROS 生产。此外，解偶联蛋白2（UCP2），一种诱导质子泄漏和的线粒体蛋白在弧形核中高度表达，减少了ROS的产生。我们发表的（Coppola等，2007； Andrews等，2008； Diano等，2011； Dietrich等人，2013年； Long等，2014）和初步数据在此资金期间产生根据生物体的代谢状态：虽然在负能量平衡期间，其特征是 AGRP增加并降低了POMC神经元活性，线粒体大小降低（裂变），期间 AGRP和POMC（融合）中线粒体大小的正能平衡（喂养状态）。因此，我们假设POMC和NPY/AGRP神经元的活性水平需要UCP2介导的线粒体动力学。 UCP2诱导的线粒体裂变，通过降低ROS产生，抑制POMC神经元而激活NPY/AGRP神经元。此外，我们假设燃料可用性驱动线粒体动力学更具体地，低葡萄糖水平驱动裂变，而高葡萄糖的可用性则驱动融合。为了测试我们的假设，即UCP2介导的线粒体动力学的燃料调节是一种代谢中心调节中的重要组成部分，提出了3个目标： AIM 1将测试UCP2介导的线粒体裂变灭活POMC神经元的假设。 AIM 2将测试UCP2介导的线粒体裂变激活NPY/AGRP的假设神经元。 AIM 3将检验以下假设：燃料可用性驱动AGRP和 POMC神经元。具体而言，我们假设低葡萄糖和高脂肪酸环境（负能量平衡）驱动裂变，而高葡萄糖可用性驱动融合。这些研究的执行将提供对全身葡萄糖中心调节的新见解代谢，并通过靶向脑线粒体动力学来打击糖尿病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Central anorexigenic actions of bile acids are mediated by TGR5.

DOI：
10.1038/s42255-021-00398-4
发表时间：
2021-05
期刊：
Nature metabolism
影响因子：
20.8
作者：
Perino A;Velázquez-Villegas LA;Bresciani N;Sun Y;Huang Q;Fénelon VS;Castellanos-Jankiewicz A;Zizzari P;Bruschetta G;Jin S;Baleisyte A;Gioiello A;Pellicciari R;Ivanisevic J;Schneider BL;Diano S;Cota D;Schoonjans K
通讯作者：
Schoonjans K

Hormonal regulation of the hypothalamic melanocortin system.