Regulatory role of CD40 in obesity-induced insulin resistance

Excessive nutrient intake in obesity triggers the accumulation of various types of immune cells in adipose tissue, particularly visceral adipose tissue (VAT). This can result in chronic inflammation which disrupts insulin effects on adipocytes and muscle cells and culminates in development of insulin resistance. The interplay between immune cells and adipose tissue is a key event for the development of insulin resistance that precedes type 2 diabetes. CD40, a well-documented costimulatory receptor, is required for efficient systemic adaptive immune responses. However, we and other groups recently showed that CD40 unexpectedly ameliorates inflammation in VAT and accordingly attenuates obesity-induced insulin resistance. Specifically, although CD40 is typically considered to play its principal immune roles on B lymphocytes and myeloid cells, we found that CD40(+)CD8(+) T lymphocytes were major contributors to the protective effect. This unexpected inhibitory role of CD40 on CD8(+) T cell activation in VAT may reflect unique features of this microenvironment. Additional knowledge gaps include whether CD40 also plays roles in mucosal immunity that control the homeostasis of gut microbiota, and human metabolic diseases. Potential therapeutic approaches, including stimulating CD40 signaling and/or manipulating specific CD40 signaling pathways in the VAT microenvironment, may open new avenues for treatment of obesity-induced insulin resistance, and prevention of type 2 diabetes.