Mitochondrial K+ Channels as Anti-Obesity Drug Targets

线粒体 K 通道作为抗肥胖药物靶点

基本信息

批准号：
10242449
负责人：
Paul S Brookes
金额：
$ 19.25万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2020-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242449
关键词：
2,4-Dinitrophenol ATP Synthesis Pathway Adipose tissue Adult Agonist Anti-Obesity Agents Belief Biochemistry Blood Glucose Body fat Cell physiology Cells Chemicals Clinical Coupling Data Diabetes Mellitus Dinitrophenols Disease Dose-Limiting Drug Screening Drug Targeting Electron Transport Enzymes Epoxide hydrolase Equilibrium Exhibits Food Genes Genetic Polymorphism Genus Hippocampus Goals High Fat Diet Human Link Lipids Medical Membrane Metabolic Metabolic Diseases Metabolism Mitochondria Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Organelles Oxidative Phosphorylation Pathology Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Potassium Channel Preventive Process Property Proteins Public Health Reporting Research Research Personnel Risk Factors Runaway Testing Therapeutic Toxic effect Weight cohort combat diet and exercise drug efficacy drug synthesis drug testing effectiveness testing energy balance high throughput screening inhibitor/antagonist metabolic phenotype mitochondrial K(ATP) channel mitochondrial uncoupling protein mortality new therapeutic target nitazoxanide novel obesity treatment oligomycin sensitivity-conferring protein oxidation public health intervention side effect stem uncoupling protein 1

项目摘要

Despite public health intervention efforts, the global burden of metabolic diseases such as type-II diabetes continues to rise, and a major risk factor for such diseases is obesity. This project explores novel drug targets in mitochondria that can modulate whole-body energy balance, a key determinant of obesity. In mitochondrial energetics, coupling between fuel oxidation and ATP synthesis occurs via a trans-membrane H+ gradient, and the uncoupling of mitochondria to dissipate this H+ gradient as heat has long been viewed as a potential drug target to alter whole-body energy balance. However, direct chemical uncouplers (e.g., dinitrophenol) are plagued by fatal dose-limiting toxicity, and mitochondrial uncoupling proteins (UCPs) have not yet delivered on their initial promise as obesity drug targets. A potential uncoupling pathway that has been largely ignored is mitochondrial K+ channels, whose opening in concert with the mitochondrial K+/H+ exchanger could uncouple mitochondria. Recently we reported a Na+ activated K+ channel (KNa1.2, Kcnt2 gene) exists in mitochondria, and that KNa channel agonists can uncouple in wild-type (WT) but not Kcnt2-/- cells. In addition, Kcnt2-/- mice have elevated body fat and dysregulated blood glucose. They also gain more weight and exhibit more hepatosteatosis (vs. WT) on a high fat diet (HFD). Furthermore, recent reports of compounds exhibiting therapeutic benefits in HFD-fed mice, have overlooked that these compounds are KNa channel openers. Another K+ channel found in mitochondria is KCa1.1 (Kcnma1 gene), and notably Kcnma1-/- mice are obese and human Kcnma1 polymorphisms are linked to obesity. Certain reactive lipids can open KCa channels, including those in mitochondria, and inhibitors of soluble epoxide hydrolase (sEH, the enzyme that degrades these lipids) are beneficial against HFD-induced pathology. This suggests mitochondrial K+ channel uncoupling as a mechanism of action for such drugs. Overall, we hypothesize that mito-K+ channels represent a novel uncoupling pathway and potential anti-obesity drug target. Aim 1 will focus on mito-KNa1.2, aiming to develop novel mitochondria-targeted KNa agonists, to be screened using WT and Kcnt2-/- mice. Aim 2 focuses on mito-KCa1.1, testing drug efficacy in WT and Kcnma1-/- mice. Our goal is to develop mito-K+ agonists as a novel class of anti-obesity drugs.

尽管采取了公共卫生干预措施，二型糖尿病等代谢性疾病的全球负担仍在持续上升，而肥胖是此类疾病的主要危险因素。该项目探索线粒体中的新药物靶点，这些靶点可以调节全身能量平衡，这是肥胖的关键决定因素。在线粒体能量学中，燃料氧化和 ATP 合成之间的耦合通过跨膜 H+ 梯度发生，并且线粒体解偶联以消散这种 H+ 梯度，因为热量长期以来一直被视为改变全身能量平衡的潜在药物靶标。然而，直接化学解偶联剂（例如二硝基苯酚）受到致命的剂量限制毒性的困扰，而线粒体解偶联蛋白（UCP）尚未兑现其作为肥胖药物靶点的最初承诺。一个在很大程度上被忽视的潜在解偶联途径是线粒体 K+ 通道，其与线粒体 K+/H+ 交换器协同开放可以解偶联线粒体。最近我们报道了线粒体中存在Na+激活的K+通道（KNa1.2，Kcnt2基因），并且KNa通道激动剂可以在野生型（WT）细胞中解偶联，但不能在Kcnt2-/-细胞中解偶联。此外，Kcnt2-/-小鼠体脂升高且血糖失调。在高脂肪饮食 (HFD) 下，他们的体重也会增加，并表现出更多的肝脂肪变性（与 WT 相比）。此外，最近关于化合物对 HFD 喂养的小鼠表现出治疗效果的报道忽略了这些化合物是 KNa 通道开放剂。线粒体中发现的另一个 K+ 通道是 KCa1.1（Kcnma1 基因），值得注意的是 Kcnma1-/- 小鼠肥胖，而人类 Kcnma1 多态性与肥胖有关。某些反应性脂质可以打开 KCa 通道，包括线粒体中的通道，而可溶性环氧化物水解酶（sEH，降解这些脂质的酶）的抑制剂有利于对抗 HFD 诱导的病理。这表明线粒体 K+ 通道解偶联是此类药物的作用机制。总的来说，我们假设 mito-K+ 通道代表了一种新的解偶联途径和潜在的抗肥胖药物靶点。目标 1 将重点关注 mito-KNa1.2，旨在开发新型线粒体靶向 KNa 激动剂，并使用 WT 和 Kcnt2-/- 小鼠进行筛选。目标 2 重点关注 mito-KCa1.1，在 WT 和 Kcnma1-/- 小鼠中测试药物疗效。我们的目标是开发 mito-K+ 激动剂作为一类新型抗肥胖药物。