Abstract 003: The Impact of MHCII Loss in Myeloid Cells and Adipocytes on Atherosclerosis and Liver Fat Accumulation

The adipocyte is capable of functioning as an antigen presenting cell in the setting of diet induced obesity in both mouse models and humans; this adipocyte activity instigates adipose tissue (AT) inflammation. To determine the relative roles of adipocyte vs. myeloid adaptive immunity on obesity-associated complications, we investigated myeloid vs. adipocyte-specific knockout of a major histocompatibility II (MHCII) protein, H2Ab1, which in mice prevents antigen presentation. Loss of adipocyte, but not myeloid, MHCII led to improvements in insulin sensitivity, adipose tissue inflammation and inhibited the shift from anti to pro-inflammatory immune cells in adipose tissue during high fat diet feeding. Both models were placed on a pro-atherogenic background (LDLR -/-), then aged for one year to accelerate atherosclerosis and were fed a western diet high in cholesterol and fat for 12 weeks. Adipocyte specific, but not myeloid specific, loss of MHCII in LDLR -/- led to dramatic improvements in atherosclerosis development, liver fat accumulation and insulin sensitivity in conjunction with an increase in the adipose tissue Tregs and a decrease in the pro-inflammatory adipocyte cytokine gene expression with no differences noted in body weight or fat. Whereas in LDLR -/- with lack of myeloid MHCII compared to LDLR -/- , we saw no differences in liver fat accumulation, atherosclerosis development or insulin sensitivity with a decrease in the anti-inflammatory Tregs, a comparable increase in adipocyte pro-inflammatory cytokine expression, but a decrease in the pro-inflammatory M1 like macrophages. These studies highlight the importance of the adipocyte as a functional contributor to the development of obesity related complications and provide a potential targeted therapeutic avenue in the management of these metabolic diseases.