The recruitment of immune cells into adipose tissue is a hallmark of obesity and a key event contributing to the development of adipose tissue inflammation and insulin resistance. However, the mechanisms regulating functions of immune cells in adipose tissue niches in response to obesity are poorly understood. In the present studies, I have demonstrated that hematopoietic-specific microRNAs and a functional cytokine, interferon tau, act as critical regulators for activation of adipose tissue resident immune cells including macrophages and B cells which subsequently affect obesity-induced tissue inflammation and insulin resistance. First, miR-150KO mice display exacerbated obesity-induced tissue inflammation and insulin resistance. This phenotype is recapitulated by the adoptive transplantation of isolated miR-150KO B cells from obese mice into mice lacking B lineage cells. Further, miR-150KO B cells exerted potent stimulatory effects on both T cells and macrophages. Several miR-150 target genes were identified and knockdown of those genes individually or in combination alleviated B cell actions upon stimulation by altering important pathways downstream of the B cell receptor complex. Second, I have shown that miR-223 is a critical mediator for PPAR? action in controlling M2 activation, and subsequent beneficial effects that mitigate tissue inflammation and insulin resistance. Impaired PPAR? functions were observed in miR-223KO mice with respect to suppression of inflammation and insulin sensitivity. Disruption of miR-223 in macrophages impaired PPAR?-dependent M2 activation, whereas overexpression of miR-223 further enhanced PPAR?-mediated M2 activation. miR-223 is a PPAR?-induced gene during M2 activation as confirmed by chromatin immunoprecipitation analysis and luciferase reporter assays. Two new miR-223 target genes Rasa1 and Nfat5 are crucial regulators of M2 activation via the PPAR?-miR-223 axis. Third, using a diet-induced obese mouse model, I discovered enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, and this was accompanied by a significant decrease in secretion of proinflammatory cytokines and an increase in M2 macrophages in adipose tissue. Further studies revealed that IFNT is a potent regulator of macrophage activation that favors M2 responses. Collectively, the findings from these thesis studies open a window to the development of novel therapeutic strategies to mitigate obesity-related diseases.
