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.

来自我们和其他实验室的先前数据(Andrews等人，2008；Benani等人，2007；Anderson等人， 2009年；Jaillard等人，2009年；Campanucci等人，2010年；Diano等人，2011年；Dietrich等人，2013年；Long等人， 2014)表明，活性氧物种(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 新陈代谢。我们观察到，抑制ROS水平会减少前阿片黑素皮质素(POMC)细胞 激活和促进神经肽Y(NPY)/刺鼠相关肽(AgRP)神经元活性和 摄食，而ROS激活POMC神经元，减少摄食。线粒体是主要细胞器 在ROS和线粒体动力学的产生中，即分裂和融合，改变了 线粒体ROS，线粒体分裂减少，线粒体融合增加 制作。此外，解偶联蛋白2(UCP2)，一种导致质子泄漏的线粒体蛋白和 在弓状核中高表达，减少ROS的产生。我们出版的(科波拉等人，2007年； Andrews等人，2008；Diano等人，2011；Dietrich等人，2013；Long等人，2014)和初步数据 显示AgRP和POMC神经元的线粒体大小发生了变化 根据机体的代谢状态：在能量负平衡期间，其特点是 AgRP增加，POMC神经元活性降低，线粒体尺寸减小(分裂)，在 正能量平衡(FED状态)AgRP和POMC线粒体尺寸增大(融合)。因此，我们 假设POMC和NPY/AgRP神经元的活动水平需要UCP2介导的线粒体 动力学。UCP2诱导的线粒体分裂，通过减少ROS的产生，抑制POMC神经元 而激活NPY/AgRP神经元。此外，我们假设燃料的供应驱动线粒体 动力学，更具体地说，低糖水平推动分裂，而高葡萄糖利用率推动融合。 为了验证我们的假设，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： 目的1验证UCP2介导的线粒体分裂使POMC神经元失活的假说。 目的2将验证UCP2介导的线粒体分裂激活NPY/AgRP的假设 神经元。 AIM 3将验证燃料供应驱动AgRP和AFP中线粒体动力学的假设 POMC神经元。具体地说，我们假设低糖和高脂肪酸环境 (负能量平衡)推动分裂，而高葡萄糖可获得性推动融合。 这些研究的实施将为全身葡萄糖的中枢调节提供新的见解 新陈代谢，并提供了新的途径，通过靶向脑线粒体动力学来对抗糖尿病。

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