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Type 2 diabetes (T2D) associates with increased risk for atherosclerosis; however, mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. In this study, using a proteomics approach we show that diet-induced obesity and insulin resistance (obesity/IR) modulates a pro-atherogenic, “macrophage-sterol-responsive-network” (MSRN), which in turn, predisposes macrophages to cholesterol accumulation. We identify IFNgamma as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation, and show that obesity/IR primes T-cells to increase IFNgamma production. Accordingly, myeloid cell-specific deletion of IFNgamma receptor (Ifngr1-/-) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis. Our findings uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr-/- mice with obesity/IR, but does not affect these parameters in Ldlr-/- mice without obesity/IR. Further, we show that obesity/IR-induced IFNgamma targets the MSRN through a host defense-independent pathway in macrophages. This pro-atherosclerotic property of IFNgamma occurs at ‘metabolic disease-appropriate’ doses without the induction of canonical IFNgamma signaling, through a post-transcriptional mechanism. Collectively, our findings identify an IFNgamma-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis.


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