2061-LB: Secreted EMC10 (scEMC10) Suppresses Thermogenesis in Brown Adipose Tissue via the Inhibition of PKA-CREB/p42 MAPK Signaling

Brown adipose tissue (BAT) plays a significant role in regulating energy metabolism, contributing to improved glucose homeostasis and reduced weight gain. We have shown Emc10 gene knockout or antibody neutralization of circulating scEMC10 prevent diet-induced obesity and its associated metabolic disorders in mouse via activation of BAT thermogenesis. In this study, we observed serum scEMC10 levels were significantly elevated by thermoneutrality, concomitant with suppression of active BAT in BAT-positive humans. Overexpression of scEMC10 promoted mouse diet-induced obesity via suppression of BAT thermogenesis, evidenced by reduced expression of UCP1 and PGC1α in BAT. scEMC10 overexpression also resulted in cold intolerance of HFD-fed mouse due to decreased levels of UCP1 and PGC1α in both epididymal adipose tissue and BAT, suggesting the involvement of scEMC10 in the sympathetic nervous system/norepinephrine-modulated BAT thermogenesis. Recombinant scEMC10 protein significantly suppressed CL 316243, a β3-adrenoceptor agonist, -induced expression of thermogenic (Ucp1, Pgc 1 ɑ, and Dio2) and lipolytic (Hsl and Atgl) genes via inhibiting PKA-CREB/p42 MAPK signaling in both cultured brown adipocyte in vitro and BAT in vivo. In conclusion, this work identifies scEMC10 exerts an inhibitory role in BAT thermogenesis via suppression of PKA-CREB/p42 MAPK signaling, and also suggests the inhibition of circulating scEMC10 will be a promising way to treat obesity and its related cardiometabolic diseases. Disclosure X. Wang: None. Y. Wang: None. S. Liu: None. C. Zhan: None. Q. Miao: None. Funding National Natural Science Foundation of China (81800691), Science and Technology Commission of Shanghai Municipality (22140902700).