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

 描述(申请人提供)：有毒脂质在非脂肪组织中积累，称为脂毒性，是肥胖导致疾病的主要途径。一种治疗肥胖相关疾病的方法，包括2型糖尿病，是扩大脂肪组织在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。临床前对β3-肾上腺素能激动剂和脂肪组织中脂肪酶过度表达的研究表明，脂肪细胞脂解的激活足以增加能量消耗，从而减少肥胖和改善全身代谢。最近的发现表明，脂肪细胞的脂肪分解和脂肪氧化可能是由从Perilipin1(PLIN1)释放ABHD5的药物刺激的，这种化合物可能被开发出来用于治疗肥胖相关的疾病。对NIH 360,000个化合物文库的筛选确定了5个这样的化合物，代表了三个不同的化学支架。初步的构效关系实验表明，该化学支架是以机理为基础的，易于化学改进。该项目的总体目标是提供ABHD5/PLIN1相互作用的早期药理学验证，作为治疗肥胖症和肥胖相关疾病的治疗目标。

 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.