PROJECT SUMMARY Obesity, an epidemic affecting more than one third of the US population, is a major risk factor for metabolicdisorders including type 2 diabetes and cardiovascular disease. Protein secreted from metabolic organsincluding adipokines, myokines, hepatokines and cardiokines are known to play important roles in inter-organscommunication leading to fine-tuning and maintenance of glucose and energy homeostasis in the body. Inaddition, many of these secreted proteins have been shown to be excellent biomarkers for the diagnosis ofmetabolic dysfunction and can be potential therapeutic targets. In a screen to identify differentially regulatedgenes in adipose tissue during obesity, we observed that the expression of a secreted endoplasmic reticulum(ER)-associated protein, Emc10 (also known as Inm02, hHss1 and Mirta22), is specifically downregulated inthe subcutaneous fat in obese mice and human. Consistent with a decreased in Emc10 expression in adiposetissues, circulating levels of Emc10 are also downregulated in obese mice. To investigate the role of Emc10 onmetabolic homeostasis, we generated Emc10 global knockout (KO) mouse. Surprisingly, in our preliminarystudies, we observed that disruption of Emc10 in mice results in protection from diet-induced obesity andmetabolic dysfunction. Further, we revealed that obesity resistance phenotype observed in Emc10 KO iscontributed by increase in oxygen consumption and simultaneous modulation of lipolysis and lipogenesis afterHFD feeding. In this proposal, we will determine the role of Emc10 on energy metabolism with three specificaims. In Aim 1, we will determine the physiological impact of Emc10 KO on energy and metabolic homeostasisin both male and female animals by subjecting them to dietary treatment. In addition we will determine thecellular processes regulated by Emc10 ablation and whether the KO mice are more susceptible to browninginduction. In Aim 2, we will determine the role of circulating Emc10. Confirmation of extracellular role of Emc10on energy homeostasis would facilitate the use of Emc10 as potential therapeutic targets. We will alsodetermine whether downregulation of Emc10 in mice fed HFD is a compensatory response to counteractobesity and finally, we will find out whether ablation of Emc10 in obese mice would prevent further weight gainand perhaps promote weight loss. In Aim 3, we will examine whether AMPK and CREB signaling pathways areinvolved the regulation of Emc10 on energy metabolism. Results from our proposed experiments will likelyprovide insights on regulatory mechanisms of Emc10 on energy and metabolic homeostasis and likely toreveal approaches for novel therapeutic strategy.
|Effective start/end date||7/1/16 → 4/30/21|
- National Institutes of Health: $359,775.00
AMP-Activated Protein Kinases
Type 2 Diabetes Mellitus