Proteins secreted from metabolic organs play critical roles in fine-tuning and maintenance of systemic metabolic and energy homeostasis. In this study, we identified a novel obesity-regulated circulating protein, scEmc10 (secreted-isoform of endoplasmic reticulum membrane complex subunit 10), that regulates systemic energy homeostasis. We initially observed that scEmc10 is modulated in adipose tissues in diet-induced obesity (DIO) models and subsequently in obese patients. Using an in-house-developed chemiluminescent immunoassay, we found that circulating Emc10 is significantly upregulated in overweight and obese patients and can be normalized by bariatric surgery-induced weight loss. Subsequently, we observed that ablation of Emc10 protects mice from DIO and associated metabolic dysregulation. Conversely, enhanced circulating Emc10 by expression of secretable AAV-hscEmc10 in the liver promotes obesity and associated metabolic dysfunctions in mice fed with either chow or high fat diet. Subsequent metabolic analysis revealed that Emc10 KO mice on HFD have elevated whole body energy expenditure compared to WT controls via an increase in oxygen consumption in both the brown and inguinal subcutaneous fat. Our mechanistic analysis demonstrated that ablation of scEmc10 promotes adaptive thermogenesis in adipocytes via activation of the PKA signaling pathway and its downstream targets, particularly CREB and p38MAPK. Finally, we also showed that neutralization of scEmc10 in the circulation with a monoclonal antibody reduced body weight and improved diet-induced metabolic dysfunction in obese mice. Our findings implicate Emc10 as a novel therapeutic target for counteracting the development of obesity and obesity-induced metabolic dysfunction.
Y. Li: None. X. Wang: None. G. Qiang: None. M.A. McCann: None. V. Gil: None. M. Blüher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Amgen, Novartis AG. C. Liew: None.
National Institutes of Health (R01DK090210, R01DK109015); National Natural Science Foundation of China (81070647, 81370936, 81873645, 81873853)