Zuoan Yi, Laura L. Stunz, Gail A. Bishop

Chronic inflammation in visceral adipose tissue is considered a key element for induction of insulin resistance in obesity. CD40 is required for efficient systemic adaptive immune responses, and is implicated in various inflammatory conditions. However, its role in modulating immunity in the microanatomical niches of adipose tissue remains largely undefined. Here we show that, in contrast to its well-documented co-stimulatory effects, CD40 regulates development of insulin resistance in a diet-induced obesity (DIO) mouse model, by ameliorating local inflammation in adipose tissues. CD40 deficiency (CD40KO) resulted in greater body weight gain, more severe inflammation in epididymal adipose tissue (EAT) and aggravated insulin resistance, in response to DIO. Interestingly, we found that CD40KO CD8(+) T lymphocytes were major contributors to exacerbated insulin resistance. Specifically, CD8(+) T cells in EAT of DIO CD40KO mice produced elevated chemokines and proinflammatory cytokines and were critical for macrophage recruitment. These results indicate that CD40 plays distinct roles in different tissues, and unexpectedly plays an important role in maintaining immune homeostasis in EAT. Further study of how CD40 promotes maintenance of healthy metabolism could contribute to better understanding of, and ability to therapeutically manipulate the increasing health problem of obesity and insulin resistance.