The role of Thymic Stromal Lymphopoietin (TSLP) in protection from Type II diabetes

Abstract

Abstract Within the past 30 years, obesity and associated disorders such as Type II diabetes are rapidly becoming world-wide epidemics. Type II diabetes, caused by the loss of insulin sensitivity, accounts for $327 billion annually in the U.S. Recent studies have shown that the immune system plays a critical role in regulating the metabolic function of adipose tissue. Importantly, Type II diabetes is a disease of chronic low-grade inflammation, and adipose T regulatory cells (Tregs) can help maintain insulin sensitivity by suppressing the inflammation caused by monocytes, CD8 T, and Natural Killer (NK) cells. We have previously reported that topical application of the Vitamin D3 analog MC903 induces a two-fold increase in the proportion and absolute number of Tregs systemically. MC903 induces production of the cytokine Thymic Stromal Lymphopoietin (TSLP) from skin keratinocytes, and TSLP stimulates proliferation of Tregs through activation of dendritic cells. In a model of diet-induced Type II diabetes, we found that mice on high fat diet treated with MC903 compared to vehicle demonstrate improved metabolic parameters, including increased glucose tolerance and decreased insulin resistance, decreased fasting glucose and insulin, and lower liver triglycerides. Concordantly, treatment of mice with a TSLP-expressing adeno-associated virus also induced similar results, suggesting that TSLP is sufficient to improve insulin sensitivity. Importantly, there was a robust increase in Tregs and decrease in CD8 T cells and NK cells in the adipose of MC903 and TSLP-treated mice. Together, our results suggest that activation of TSLP signaling may be a therapeutic immunotarget for improving insulin sensitivity and preventing Type II diabetes.