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The adipocyte, in addition to functioning as an energy storage cell, is an important immune cell that links the innate and adaptive immune system. In obese humans, our laboratory has previously demonstrated that the major histocompatibility complex II (MHCII) pathway is one of the most differentially expressed between lean and obese adipocytes. Further work in high fat diet fed mouse models demonstrates that increased adipocyte MHCII expression resulted in pro-inflammatory T cell differentiation leading to insulin resistance and decreased glucose tolerance. In contrast, loss of adipocyte MHCII expression in aMHCII knockout male mice resulted in less inflammatory adipose tissue characterized by increased adipose tissue immunosuppressive regulatory T cells (Tregs) and prevented the development of insulin resistance and glucose intolerance induced by Western high fat diet (WD). Moreover, these mice had less atherosclerosis and less liver steatosis and inflammation, common complications of obesity. We, thus, aimed to understand the impact of the loss of aMHCII expression in female mice on these and other inflammatory complications.

We crossed aMHCII KO mice with proatherogenic low density lipoprotein receptor knockout (LDLR-/-) mice, aged the female animals for one year to accelerate atherosclerosis and hepatic injury, and fed them WD for twelve weeks (n=12 control, n=12 aMHCII KO). Glucose (GTT) and insulin (ITT) tolerance tests, body fat composition and fasting blood were collected prior to WD start and at study end. At the time of sacrifice, visceral adipose tissue was collected for T cell flow analysis and gene expression, liver was collected for liver fat analysis and histology, and aortas were collected for atherosclerotic lesion area measurement.

Results showed that the female aMHCII KO mice experienced a significantly lower percent weight gain over 12 weeks than wild-type (control) littermate control mice, despite demonstrating no significant difference in overall percent body fat. The knockout mice additionally demonstrated improved glucose tolerance after 12 weeks of WD, compared to the control mice (AUC control = 23090.0 +/- 520.9 vs. KO= 20442.3 +/- 657.9, P=0.0045), although no difference was observed in insulin sensitivity. No difference was found in circulating plasma triglyceride or cholesterol levels; however, liver fat accumulation was significantly decreased in KO mice (control= 17.14 +/- 0.93 %fat vs. KO= 13.89 +/- 1.04 %fat, P=0.039). Finally, no difference was found in atherosclerosis % lesion area of the aorta. These results support that the adipocyte knockout of MHCII leads to improvement in the metabolic and hepatic phenotype in female mice after 12 weeks on WD. However, as the females demonstrated some variation from the effects seen in male mice, further investigation into the cause of these differences is warranted.