Preclinical validation of ABHD5 as a target for treatment of obesity.

 描述（由申请方提供）：毒性脂质在非脂肪组织中的积累，称为脂毒性，是肥胖症产生疾病的主要方式。肥胖相关疾病（包括2型糖尿病）的一种治疗方法是扩大脂肪组织原位动员和燃烧脂肪酸的能力，从而防止脂毒性脂质在其他地方积聚。β3-肾上腺素能激动剂和脂肪组织中脂肪酶过表达的临床前经验表明，脂肪细胞脂解的激活足以增加能量消耗，从而减少肥胖并改善全身代谢。最近的发现表明，脂肪细胞脂解和脂肪氧化可能被从perilipin 1（PLIN 1）释放ABHD 5的药物刺激，并且此类化合物可能被开发用于治疗肥胖相关疾病。NIH 360，000化合物库的筛选鉴定了五种这样的化合物，代表三种不同的化学支架。初步构效关系实验表明，化学支架是基于机制的，并服从化学改进。该项目的总体目标是提供ABHD 5/PLIN 1相互作用作为治疗肥胖和肥胖相关疾病的治疗靶点的早期药理学验证。

 DESCRIPTION (provided by applicant): The accumulation of toxic lipids in non-adipose tissues, termed lipotoxicity, is a major means by which obesity produces disease. One therapeutic approach to obesity-related disease, including type 2 diabetes, is to expand the ability of adipose tissues to mobilize and burn fatty acids in situ and thereby prevent lipotoxic lipid accumulation elsewhere. Preclinical experience with β3-adrenergic agonists and lipase overexpression in adipose tissue indicates that activation of adipocyte lipolysis is sufficient to increase energy expenditure which reduces obesity and improves systemic metabolism. Recent discoveries suggested that adipocyte lipolysis and fat oxidation might be stimulated by agents that release ABHD5 from perilipin1 (PLIN1), and such compounds might be developed for treatment of obesity-related disorders. Screening of the NIH 360,000 compound library identified five such compounds, representing three distinct chemical scaffolds. Initial structure-activity relations experiments demonstrate that the chemical scaffolds are mechanism-based and amenable to chemical improvement. The overall goal of this project is to provide early stage pharmacological validation of the ABHD5/PLIN1 interaction as a therapeutic target for treatment of obesity and obesity-related disease.