Endoplasmic Reticulum Membrane Protein Complex 10 (EMC10), a Novel Circulating Factor for Systemic Energy and Metabolic Homeostasis

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, EMC10, that regulates systemic energy homeostasis. We initially observed that EMC10 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. To determine the role of EMC10, we subjected Emc10 KO mice to dietary treatment. We observed that ablation of Emc10 protects mice from DIO and associated metabolic dysregulation including glucose intolerance, insulin resistance, hyperinsulinemia, hyperleptinemia, and hyperlipidemia. Conversely, enhanced circulating EMC10 by expression of secretable AAV-hEMC10 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. We showed that ablation of Emc10 not only promotes basal UCP1 and PGC1a expression but also sensitized adipocytes to beta-adrenergic stimulated thermogenic markers activation. Finally, our preliminary data showed that activation of the transcription factor CREB and p38 MAPK could potentially mediate EMC10 regulation of thermogenesis. Our findings implicate EMC10 as a novel therapeutic target for counteracting the development of obesity and obesity-induced metabolic dysfunction.