Pyrazolone derivative C29 protects against HFD-induced obesity in mice via activation of AMPK in adipose tissue  

作　　者：Bo-han Li Mei Zhang Ya-nan Duan Lin Shuai Hao-wen Jiang Jia Li Fa-jun Nan Jing-ya Li 

机构地区：[1]State Key Laboratory of Drug Research,the National Drug Screening Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Acta Pharmacologica Sinica》2021年第6期964-974,共11页中国药理学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(No.81470166 and 81273566);the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program"of China(2018ZX09711002).

摘　　要：Beige adipocytes have been considered as a potential strategy in anti-obesity therapy because of its thermogenic capacity.AMP-activated protein kinase(AMPK)plays important roles in regulating adipose tissue function.C29 is a novel pyrazolone derivative with AMPK activity.In the current study,we investigated the role of C29 in the regulation of thermogenesis using differentiated adipocytes and diet-induced obese mice,and explored the mechanisms that might be involved in energy expenditure via adipocyte AMPK activation.We showed that treatment with C29(2.5–10μM)concentration-dependently increased thermogenesis in differentiated preadipocytes separated from inguinal white adipose tissue(iWAT),evidenced by increased expression levels of thermogenesis markers such as Ucp1,Pgc-1α,Dio2,Prdm16,Cox7a1,Cox8b,Elovl3,and Cidea,fatty acid oxidation(FAO)genes including Cpt1a,Lcad and Pparα,as well as beige-selective genes such as Cd137,Tmem26,Slc27a1,and Tbx1.In high-fat diet(HFD)-fed mice,oral administration of C29(30 mg·kg^(−1)·day^(−1))for 9 weeks alleviated HFD-induced obesity,promoted energy expenditure and modulated iWAT browning.However,these effects were not observed in adipose-specific AMPKα1/α2 knockout(AKO)mice following C29 administration.Together,this study demonstrates that C29 regulates energy balance via adipocyte AMPK.Our findings show that the discovery of AMPK activators that specifically target adipose tissue may have therapeutic potential for treating obesity-related metabolic diseases.

关 键 词：AMP-activated protein kinase pyrazolone derivative C29 OBESITY energy expenditure THERMOGENESIS inguinal white adipose tissue white adipose browning 

分 类 号：R965[医药卫生—药理学]