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.