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

肥胖和超重影响着世界三分之一以上的人口，是肥胖和超重的重要危险因素。 多种合并症，包括心血管疾病、癌症和糖尿病。常见的肥胖症通常是 伴随着哺乳动物中主要的脂肪抑制因子瘦素的循环水平升高。方法 增加瘦素敏感性可以代表治疗肥胖的安全和有效的方法。这项建议 提出了令人信服的新的初步数据表明，外周管理的一个特定的组蛋白， 去乙酰化酶6（HDAC 6）抑制剂（Tubastatin A）对饮食诱导的肥胖小鼠抑制食物摄入， 以HDAC 6依赖的方式减少肥胖，脂肪量减少高达50%。这些 改善伴随着显著减少的肝脂肪变性和改善的全身葡萄糖 体内平衡Tubastatin不会诱导瘦素受体突变型db/db小鼠或瘦野生型小鼠的体重减轻 小鼠，但增加了动物对外源性瘦素给药的敏感性。Tubastatin诱导的代谢 改善独立于中心HDAC 6活性，并且在很大程度上取决于脂肪组织HDAC 6 表情本申请集中于外周HDAC 6抑制赋予 中枢瘦素敏化，并提出确定解剖（目标1）和分子（目标2）机制 HDAC 6抑制介导的肥胖和糖尿病的改善， 药理学和生物化学方法。目的3探讨瘦素增敏的中枢介质， 以及HDAC 6抑制剂如何潜在地改变血脑屏障通透性。它将进一步研究 非受体酪氨酸激酶Pyk 2作为一种潜在的新型调节剂或瘦素受体信号转导。这 一项提案提出HDAC 6作为一种新的能量稳态调节剂，并作为一个潜在的目标， 开发针对肥胖症的新治疗方法。更一般地说，这项工作将建立一个 肥胖症和饮食失调治疗的基础和临床研究的基础平台。

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.