| Summary: | Adipose tissue macrophage (ATM) inflammation associates with obesity, insulin resistance, and type II diabetes. However, in humans, molecular mechanisms linking ATM inflammation and insulin resistance remain poorly defined. This is due, in part, to our limited understanding of mechanisms driving ATM inflammation in vivo. To interrogate potential pathways of ATM inflammation, we used proteomics to define plasma membrane protein signatures of human monocyte-derived macrophages treated with INFgamma+LPS ("classical activation") or glucose+insulin+palmitate ("metabolic activation"). Although both stimuli similarly induced pro-inflammatory cytokine expression, cell surface expression patterns were remarkably distinct. To provide physiological relevance we demonstrate that protein signatures of classical activation are readily detectable in alveolar macrophages of patients with cystic fibrosis (chronic bacterial infection). Markers of metabolic activation are expressed by ATMs in obese humans and mice and positively correlate in adiposity and inflammation. Metabolic activation is driven by competing pro- and anti-inflammatory pathways, which regulate balance between cytokine production and lipid metabolism. We identify macrophage ROS producing, NOX2 a key regulator of metabolic activation. To define the contribution of metabolic activation to insulin resistance whole animal Nox2-/- mice were placed on a 45% high-fat diet for 16 weeks, and metabolic parameter assessed at 8 and 16 weeks. Ablation of metabolic activation in vivo resulted in a complex phenotype dependent upon duration of high-fat feeding. Data presented here stress the importance of fully defining the mechanisms responsible for metabolic activation and their effect on insulin sensitive tissues prior to therapeutic intervention.
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