A Distinct Population of Lipid Sensing iNKT Cells are Enriched in Fat and Protect Against Diet-Induced Obesity and Insulin Resistance (176.26)

Abstract

Immunometabolic interactions regulate adipose tissue inflammation in obesity and subsequent development of insulin resistance. We have shown that human and murine fat contains the largest population of iNKT cells in the body. Fat resident iNKT cells are a distinct subset with unique phenotype and anti-inflammatory cytokine profile. These iNKT cells are depleted in diet-induced obesity and removal of high fat diet results in iNKT restoration in mice and humans. Furthermore, mice lacking iNKT cells have enhanced weight gain, larger adipocyte size, fatty liver infiltration and insulin resistance. Adoptive transfer of iNKT from WT mice into obese mice or activation of remaining iNKT in obese fat by through injection of alpha- galactosylceramide (aGC) had a profound improvement in insulin sensitivity and glucose handling, a decrease in serum triglycerides, leptin, body fat, fatty liver infiltration and proinflammatory macrophage levels. It is therefore beneficial to identify what causes iNKT cells depletion in obesity. We have purified lipids from obese and lean adipose tissue, to identify which, if any, lipid fraction may activate iNKT cells. Early preliminary data suggest that a HFD abherrently activate iNKT cells in obesity, leading to their loss, and subsequent development of insulin resistance. In summary, we have identified a distinct population if iNKT cells in fat and describe a unique role for iNKT in protection against obesity and related metabolic disease. .