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

肥胖和超重影响着世界上三分之一以上的人口，是患高血压的重要风险因素 心血管疾病、癌症和糖尿病等合并症的数量。常见的肥胖通常是 伴随着循环中瘦素水平的升高，瘦素是哺乳动物的主要脂肪因子。方法 增强瘦素的敏感性可能是治疗肥胖的安全有效的手段。这项建议 提供了令人信服的新的初步数据，表明特定组蛋白的外周给药 脱乙酰酶6(HDAC6)抑制剂Tubasatin A对饮食诱导的肥胖小鼠的摄食和抑制作用 以依赖HDAC6的方式减少肥胖，脂肪质量减少高达50%。这些 改善伴随着肝脏脂肪变性的显著减轻和全身血糖的改善。 动态平衡。Tubasatin不会导致瘦素受体突变db/db小鼠体重减轻，也不会导致瘦身野生型 但会增加动物对外源性瘦素注射的敏感性。图巴斯汀诱导的代谢 改善与中枢HDAC6活性无关，在很大程度上取决于脂肪组织HDAC6 表情。目前的应用集中在外周HDAC6抑制带来的假设上 中枢瘦素敏感化，并建议确定解剖学(目标1)和分子(目标2)机制 HDAC6抑制介导的肥胖和糖尿病的改善使用遗传， 药理和生化方法。目标3将探索瘦素敏化的中枢介质， 以及HDAC6抑制剂如何潜在地改变血脑屏障的通透性。它将进一步研究这一角色 非受体酪氨酸激酶PYK2作为一种潜在的新的调节因子或瘦素受体信号。这 提案将HDAC6作为一种新的能量动态平衡调节器，并作为 开发治疗肥胖症的新方法。更广泛地说，这项工作将建立一个 治疗肥胖和饮食失调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.