Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity

HDAC6 在能量稳态和瘦素敏感性调节中的作用

基本信息

批准号：
10352472
负责人：
Roger D. Cone
金额：
$ 39.48万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352472
关键词：
Acyl Coenzyme A Adipose tissue Adult Affect Anatomy Animals Anti-Obesity Agents Antidiabetic Drugs Applications Grants Attenuated Basic Science Binding Biochemical Blood Body Weight Body Weight decreased Brain Brain region Cardiovascular Diseases Cells Clinical Research Data Deacetylase Development Diabetes Mellitus Diazepam Binding Inhibitor Disease Drug Targeting Eating Eating Disorders Economic Burden Energy Metabolism Fatty Liver Fatty acid glycerol esters Functional disorder Genes Genetic Genetic Transcription HDAC6 gene Heat-Shock Response Homeostasis Hormones Hypothalamic structure Knockout Mice Lead Leptin Leptin resistance Liver Maintenance Malignant Neoplasms Mammals Mediating Mediator of activation protein Metabolic Methods Modeling Molecular Mus Neurons Obese Mice Obesity Obesity Epidemic Outcomes Research Overweight Oxidative Stress Pathway interactions Peripheral Pharmacology Phenotype Population Process Receptor Signaling Regulation Resistance Risk Factors Rodent Model Role Signal Transduction Site Stress Testing Therapeutic Thinness Tissues Transcript Wild Type Mouse Work base biological adaptation to stress blood glucose regulation blood-brain barrier permeabilization brain cell combat comorbidity db/db mouse design diabetic diet-induced obesity drug action heat-shock factor 1 improved inhibitor leptin receptor mouse model mutant novel novel therapeutic intervention nuclear factor-erythroid 2 obese person obesity treatment paralogous gene prevent proteostasis public health relevance response small molecule transcriptome transcriptomics

项目摘要

Obesity and overweight affect more than one third of the world population, and are significant risk factors for a number of comorbidities including cardiovascular disease, cancer and diabetes. Common obesity is usually accompanied by elevated circulating levels of leptin, the primary adipostatic factor in mammals. Methods augmenting leptin sensitivity may represent safe and effective means of treating obesity. This proposal presents compelling new preliminary data showing that peripheral administration of a specific histone deacetylase 6 (HDAC6) inhibitor (Tubastatin A) to diet-induced obese mice suppresses food intake and reduces obesity, in an HDAC6-dependent manner, with up to 50 percent decrease in fat mass. These improvements are accompanied by significantly reduced hepatic steatosis, and improved systemic glucose homeostasis. Tubastatin does not induce weight loss in leptin receptor mutant db/db mice, or lean wild type mice, but increases the sensitivity of animals to exogenous leptin administration. Tubastatin-induced metabolic improvements are independent of central HDAC6 activity, and in large part depends on adipose tissue HDAC6 expression. The current application is centered on the hypothesis that peripheral HDAC6 inhibition confers central leptin sensitization, and proposes to identify the anatomical (Aim 1) and molecular (Aim 2) mechanisms of HDAC6 inhibition-mediated amelioration of obesity and diabetes using a combination of genetic, pharmacological and biochemical approaches. Aim 3 will explore the central mediators of leptin sensitization, and how blood brain barrier permeability is potentially altered by HDAC6 inhibitors. It will further study the role of the non-receptor tyrosine kinase Pyk2 as a potentially novel regulator or leptin receptor signaling. This proposal presents HDAC6 as a novel regulator of energy homeostasis and as a potential target for development of novel therapeutic approaches against obesity. More generally, this work will establish a fundamental platform for basic and clinical research for the treatment of obesity and eating disorders.

肥胖和超重影响世界人口的三分之一以上，是一个重要的风险因素合并症的数量，包括心血管疾病，癌症和糖尿病。普通肥胖通常是伴随着瘦素的循环水平升高，瘦素是哺乳动物的主要脂肪因子。方法增强瘦素敏感性可能代表了治疗肥胖症的安全有效手段。这个建议提出引人注目的新初步数据，表明特定组蛋白的外围给药脱乙酰基酶6（HDAC6）抑制剂（tubastatin a）以饮食诱导的肥胖小鼠抑制食物摄入量和以HDAC6依赖性方式降低肥胖症，脂肪质量降低50％。这些改进伴随着明显降低的肝脂肪变性，并改善了全身葡萄糖稳态。 tubastatin不会诱导瘦素受体突变体DB/dB小鼠的体重减轻，或瘦的野生型小鼠，但增加了动物对外源瘦素给药的敏感性。图拜汀诱导的代谢改进与中央HDAC6活性无关，很大程度上取决于脂肪组织HDAC6 表达。当前的应用集中在外围HDAC6抑制概述的假设上中央瘦素敏化，并提出识别解剖学（AIM 1）和分子（AIM 2）机制 HDAC6抑制介导的肥胖和糖尿病的改善，结合了遗传，药理和生化方法。 AIM 3将探索瘦素致敏的中心介体， HDAC6抑制剂可能会改变血脑屏障的渗透率。它将进一步研究角色非受体酪氨酸激酶PYK2作为潜在的新型调节剂或瘦素受体信号传导。这提案将HDAC6作为能量稳态的新型调节剂，并作为潜在的目标开发针对肥胖症的新型治疗方法。更一般地，这项工作将建立一个基础和临床研究的基本平台，用于治疗肥胖和饮食失调。