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: 9333677
• 负责人: Sabrina Diano
• 金额: $ 49.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333677
• 关键词: Affect; Animal Feed; Brain; Carbohydrates; Cells; Data; Diabetes Mellitus; Diet; Energy Metabolism; Environment; Etiology; Fatty Acids; Funding; Generations; Glucose; Hypothalamic structure; Knockout Mice; Laboratories; Leptin; Leptin resistance; Lipids; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Proteins; Mus; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Organism; Peptides; Peripheral; Peroxisome Proliferation; Play; Pro-Opiomelanocortin; Production; Protons; Publishing; Reactive Oxygen Species; Regulation; Role; Structure of nucleus infundibularis hypothalami; Testing; UCP2 protein; blood glucose regulation; combat; energy balance; experimental study; feeding; glucose metabolism; insight; neuronal circuitry; neuropeptide Y; novel; obesity treatment; overexpression; oxidation; response; selective expression; treatment strategy

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，