Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice

Xuanchun Wang (), Yanliang Li, Guifen Qiang, Kaihua Wang, Jiarong Dai, Maximilian McCann, Marcos D. Munoz, Victoria Gil, Yifei Yu, Shengxian Li, Zhihong Yang, Shanshan Xu, Jose Cordoba-Chacon, Dario F. Jesus, Bei Sun, Kuangyang Chen, Yahao Wang, Xiaoxia Liu, Qing Miao, Linuo Zhou, Renming Hu, Qiang Ding, Rohit N. Kulkarni, Daming Gao, Matthias Blüher and Chong Wee Liew ()
Additional contact information
Xuanchun Wang: Fudan University
Yanliang Li: Fudan University
Guifen Qiang: University of Illinois at Chicago
Kaihua Wang: Chinese Academy of Sciences
Jiarong Dai: Fudan University
Maximilian McCann: University of Illinois at Chicago
Marcos D. Munoz: University of Illinois at Chicago
Victoria Gil: University of Illinois at Chicago
Yifei Yu: Fudan University
Shengxian Li: University of Illinois at Chicago
Zhihong Yang: Harvard Medical School
Shanshan Xu: University of Illinois at Chicago
Jose Cordoba-Chacon: University of Illinois at Chicago
Dario F. Jesus: Harvard Medical School
Bei Sun: Tianjin Medical University
Kuangyang Chen: Fudan University
Yahao Wang: Fudan University
Xiaoxia Liu: Fudan University
Qing Miao: Fudan University
Linuo Zhou: Fudan University
Renming Hu: Fudan University
Qiang Ding: Fudan University
Rohit N. Kulkarni: Harvard Medical School
Daming Gao: Chinese Academy of Sciences
Matthias Blüher: University of Leipzig
Chong Wee Liew: University of Illinois at Chicago

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.

Date: 2022
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DOI: 10.1038/s41467-022-34259-9

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