The central theme of this application is to demonstrate how IEX-1 deficiency protects mice against HFD diet-induced obesity and insulin resistance. By employing a reciprocal adaptive transfer technique to specifically delete IEX-1 from hematopoietically derived cells, we will elucidate a decisive role of IEX-1 in regulation of macrophages phenotype and inflammation during high calorie consumption. This maneuver will help us delineate if IEX-1 in hematopoietically derived cells is important for development of obesity or insulin resistance. Furthermore, IEX-1 is highly expressed in mitochondria where it regulates mitochondrial respiration by promoting degradation of mitochondrial F1F0-ATPase inhibitor IF1 protein. Therefore, we suspect that IEX- 1 may have a direct role in metabolism and energy homeostasis. We will assess glucose metabolism in individual tissues and energy expenditure in the absence of IEX-1 using hyperinsulinemic-euglycemic clamp and indirect calorimetry, respectively. Lastly, to gain a mechanistic insight into how IEX-1 deficiency prevents diet-induced switch in ATM phenotype, we will employ an in-vitro forced M1 polarization techniques in bone marrow-derived macrophages co-cultured in the absence or presence of primary adipocytes. The study will provide novel insights into a mechanistic linkage between IEX-1 and metabolic function, and obesity.
Obesity is one of today's most important public health concerns as it increases the risk of premature death, diabetes and heart disease. There is an urgent need to develop novel therapeutic approaches that can prevent/reverse excessive weight gain but also target the molecular pathways that link obesity with other pathologies. IEX-1 could be one such promising molecular target. The appeal and the potential of future outcomes of this project satisfy the objectives of the NIDDK sponsored Mentored Research Scientist Development Award (KO1).