2. Academic Validation
  3. Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice

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

  • Nat Commun. 2022 Nov 28;13(1):7323. doi: 10.1038/s41467-022-34259-9.
Xuanchun Wang # 1,  Yanliang Li # 2 3 4,  Guifen Qiang # 3 5,  Kaihua Wang # 6 7,  Jiarong Dai 2,  Maximilian McCann 3 4,  Marcos D Munoz 3,  Victoria Gil 3,  Yifei Yu 2,  Shengxian Li 3 8,  Zhihong Yang 9 10,  Shanshan Xu 3,  Jose Cordoba-Chacon 11,  Dario F De Jesus 9,  Bei Sun 12,  Kuangyang Chen 2,  Yahao Wang 2,  Xiaoxia Liu 2,  Qing Miao 2,  Linuo Zhou 2,  Renming Hu 2,  Qiang Ding 13,  Rohit N Kulkarni 9,  Daming Gao 6 14,  Matthias Blüher 15,  Chong Wee Liew 16
Affiliations

Affiliations

  • 1 Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China. [email protected].
  • 2 Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Physiology & Biophysics, University of Illinois at Chicago, Chicago, IL, USA.
  • 4 Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, USA.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 7 University of Chinese Academy of Sciences, Beijing, China.
  • 8 Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 9 Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Transplant Surgery, Mass General Hospital, Harvard Medical School, Boston, MA, USA.
  • 11 Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA.
  • 12 NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
  • 13 Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
  • 14 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 15 Department of Medicine, University of Leipzig, Leipzig, Germany.
  • 16 Department of Physiology & Biophysics, University of Illinois at Chicago, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 36443308 DOI: 10.1038/s41467-022-34259-9
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.

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