Obesity, an epidemic affecting more than one third of the US population, is a major risk factor for metabolic disorders including type 2 diabetes and cardiovascular disease. Protein secreted from metabolic organs including adipokines, myokines, hepatokines and cardiokines are known to play important roles in inter-organs communication leading to fine-tuning and maintenance of glucose and energy homeostasis in the body. In addition, many of these secreted proteins have been shown to be excellent biomarkers for the diagnosis of metabolic dysfunction and can be potential therapeutic targets. In a screen to identify differentially regulated genes 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 in the subcutaneous fat in obese mice and human. Consistent with a decreased in Emc10 expression in adipose tissues, circulating levels of Emc10 are also downregulated in obese mice. To investigate the role of Emc10 on metabolic homeostasis, we generated Emc10 global knockout (KO) mouse. Surprisingly, in our preliminary studies, we observed that disruption of Emc10 in mice results in protection from diet-induced obesity and metabolic dysfunction. Further, we revealed that obesity resistance phenotype observed in Emc10 KO is contributed by increase in oxygen consumption and simultaneous modulation of lipolysis and lipogenesis after HFD feeding. In this proposal, we will determine the role of Emc10 on energy metabolism with three specific aims.
In Aim 1, we will determine the physiological impact of Emc10 KO on energy and metabolic homeostasis in both male and female animals by subjecting them to dietary treatment. In addition we will determine the cellular processes regulated by Emc10 ablation and whether the KO mice are more susceptible to browning induction.
In Aim 2, we will determine the role of circulating Emc10. Confirmation of extracellular role of Emc10 on energy homeostasis would facilitate the use of Emc10 as potential therapeutic targets. We will also determine whether downregulation of Emc10 in mice fed HFD is a compensatory response to counteract obesity and finally, we will find out whether ablation of Emc10 in obese mice would prevent further weight gain and perhaps promote weight loss.
In Aim 3, we will examine whether AMPK and CREB signaling pathways are involved the regulation of Emc10 on energy metabolism. Results from our proposed experiments will likely provide insights on regulatory mechanisms of Emc10 on energy and metabolic homeostasis and likely to reveal approaches for novel therapeutic strategy.
Obesity is a critical health problem in the US because it leads to fatal complications. These studies will determine the roles and mechanisms of a novel circulating protein, Emc10, on diet-induced obesity and metabolic dysfunction. Understanding the gene targets will shed light on development of therapeutic strategies.
|Liew, Chong Wee; Xu, Shanshan; Wang, Xuerong et al. (2017) Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy. Circ Heart Fail 10:|
|Qi, Weier; Keenan, Hillary A; Li, Qian et al. (2017) Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 23:753-762|