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Insulin resistance and type 2 diabetes have reached epidemic levels in the United States. Mouse models have demonstrated that the increase in inflammatory cytokines during obesity is a mechanistically linked to insulin resistance. Adipose tissue macrophages, which accumulate and become activated during obesity, are a major source of this inflammation. These macrophages were often thought to be classically activated. However, studies of adipose tissue macrophages in humans demonstrate that the human obese adipose tissue macrophage phenotype is less straightforward. Our lab demonstrated that these macrophages exhibit a phenotype distinct from classical activation and redefined them as metabolically activated. Here we investigate the association of surface markers of metabolic activation with insulin resistance in humans. We use flow cytometry and a host of other parameters to show that insulin resistance is associated with omental ABCA1 expression independent of changes in inflammation. We also present an unexpected and strong relationship between ABCA1 expression and omental adipocyte size. These findings reveal a novel marker associated with insulin resistance in humans and raise further questions about role of adipose tissue macrophages in this disease. In our second aim we present a series of tyrosine kinases that promote metabolic activation. We also demonstrate that metabolic activation engages the transcription factor NFB using a mechanism that is distinct from canonical NFB signaling. These findings provide new therapeutic targets to treat insulin resistance through attenuating macrophage activation. Overall, this work provides insight into the metabolic activation phenotype at multiple levels and establishes a foundation to pursue the pathways that drive it.




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