Role of Peroxisome Proliferation in Leptin Resistance

来自我们和其他实验室的先前数据（Andrews等人，2008; Benani等人，2007;安德森等人， 2009; Jaillard等人，2009; Campanucci等人，2010; Diano等人，2011; Dietrich等人，2013; Long等人， 2014）表明，活性氧（ROS）的产生不仅仅是底物的副产物， 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.我们已经观察到ROS水平的抑制减少了前阿黑皮素（POMC）细胞 激活并促进神经肽Y-（NPY）/AgRP相关肽-（AgRP）神经元的活性， 摄食，而ROS激活POMC神经元并减少摄食。线粒体是主要的细胞器 在ROS和线粒体动力学的产生中，即裂变和融合，改变了 线粒体ROS，线粒体分裂减少，线粒体融合增加ROS 生产此外，解偶联蛋白2（UCP 2），一种诱导质子泄漏的线粒体蛋白， 在弓状核中高度表达，减少ROS的产生。我们发表的（Coppola et al.，二○ ○七年; Andrews等人，2008; Diano等人，2011; Dietrich等人，2013; Long等人，2014年）和初步数据 在此资助期间产生的结果显示，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：而在负能量平衡期间，其特征在于， AgRP增加和POMC神经元活动减少，线粒体大小减少（分裂）， 正能量平衡（进食状态）线粒体大小在AgRP和POMC（融合）中增加。因此我们 假设POMC和NPY/AgRP神经元的活性水平需要UCP 2介导的线粒体 动力学UCP 2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，燃料供应驱动线粒体 动力学更具体地说，低葡萄糖水平驱动裂变，而高葡萄糖可用性驱动融合。 为了验证我们的假设，即UCP 2介导的线粒体动力学的燃料调节是一个重要的因素。 作为代谢中枢调节的重要组成部分，提出了3个目标： 目的1将检验UCP 2介导的线粒体分裂使POMC神经元失活的假设。 目的2将检验UCP 2介导的线粒体分裂激活NPY/AgRP的假设。 神经元 目的3将检验燃料可用性驱动AgRP中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，而高葡萄糖可用性驱动融合。 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 通过靶向脑线粒体动力学，提供了对抗糖尿病的新途径。

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.