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

• Published in: Acta pharmacologica Sinica Vol. 42; no. 6; pp. 964 - 974
• Main Authors: Li, Bo-Han, Zhang, Mei, Duan, Ya-Nan, Shuai, Lin, Jiang, Hao-Wen, Li, Jia, Nan, Fa-Jun, Li, Jing-Ya
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2021; Springer Singapore
• Subjects: Adipocytes; Adipocytes - drug effects; Adipose tissue; Adipose Tissue, Beige - enzymology; Adipose Tissue, Beige - metabolism; Adipose Tissue, White - drug effects; Adipose Tissue, White - enzymology; Adipose Tissue, White - metabolism; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Body Temperature - drug effects; CD137 antigen; Cell Differentiation - drug effects; Diet, High-Fat; Energy balance; Energy expenditure; Enzyme Activators - therapeutic use; High fat diet; Insulin Resistance - physiology; Kinases; Male; Metabolic disorders; Mice; Mice, Inbred C57BL; Obesity; Obesity - drug therapy; Obesity - enzymology; Obesity - metabolism; Oral administration; Oxidation; Preadipocytes; Pyrazolones - therapeutic use; Tbx1 protein; Thermogenesis; Thermogenesis - drug effects; thermogenesis; inguinal white adipose tissue; pyrazolone derivative C29; AMP-activated protein kinase; energy expenditure; white adipose browning; obesity
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00524-0

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 (2.5-10 μM) 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 ·day ) 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.