Role of peroxisome proliferation in leptin resistance

过氧化物酶体增殖在瘦素抵抗中的作用

• 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
• 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

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 等人，2008 年；Benani 等人，2007 年；Anderson 等人， 2009年； Jaillard 等人，2009；坎帕努奇等人，2010；迪亚诺等人，2011；迪特里希等人，2013；龙等人， 2014）表明活性氧（ROS）的产生不仅仅是底物的副产品 氧化，但它在调节参与能量调节的细胞反应中起着至关重要的作用 代谢。我们观察到，抑制 ROS 水平会减少阿片黑皮素原 (POMC) 细胞 激活并促进神经肽 Y- (NPY)/刺鼠相关肽- (AgRP) 神经元的活性 进食，而 ROS 激活 POMC 神经元并减少进食。线粒体是主要细胞器 在 ROS 的产生和线粒体动力学（即裂变和融合）中，改变了 线粒体 ROS，线粒体裂变减少，线粒体融合增加 ROS 生产。此外，解偶联蛋白 2 (UCP2)，一种诱导质子泄漏的线粒体蛋白， 在弓状核中高表达，减少 ROS 的产生。我们发表了（Coppola 等人，2007 年； 安德鲁斯等人，2008；迪亚诺等人，2011；迪特里希等人，2013； Long 等人，2014）和初步数据 在此资助期间产生的结果表明，AgRP 和 POMC 神经元中的线粒体大小发生了变化 根据生物体的代谢状态：在负能量平衡期间，其特点是 AgRP 增加，POMC 神经元活动减少，线粒体大小减小（裂变）， 正能量平衡（进食状态）AgRP 和 POMC（融合）中线粒体大小增加。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 诱导的线粒体分裂通过减少 ROS 产生来抑制 POMC 神经元 同时激活 NPY/AgRP 神经元。此外，我们假设燃料可用性驱动线粒体 动力学上，更具体地说，低葡萄糖水平驱动裂变，而高葡萄糖可用性驱动融合。 为了检验我们的假设，即 UCP2 介导的线粒体动力学的燃料调节是一种 代谢中枢调节的重要组成部分，提出了 3 个目标： 目标 1 将检验 UCP2 介导的线粒体裂变使 POMC 神经元失活的假设。 目标 2 将检验 UCP2 介导的线粒体裂变激活 NPY/AgRP 的假设 神经元。 目标 3 将检验燃料可用性驱动 AgRP 和线粒体动力学的假设 POMC 神经元。具体来说，我们假设低葡萄糖和高脂肪酸环境 （负能量平衡）驱动裂变，而高葡萄糖可用性则驱动聚变。 这些研究的执行将为全身葡萄糖的中枢调节提供新的见解 代谢并通过针对大脑线粒体动力学提供对抗糖尿病的新途径。

项目成果

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.

• DOI: 10.3389/fphys.2014.00480
• 发表时间: 2014
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Kim JD;Leyva S;Diano S
• 通讯作者: Diano S