Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network

Publication date: 5 June 2018
Source:Cell Reports, Volume 23, Issue 10
Author(s): Catherine A. Reardon, Amulya Lingaraju, Kelly Q. Schoenfelt, Guolin Zhou, Chang Cui, Hannah Jacobs-El, Ilona Babenko, Andrew Hoofnagle, Daniel Czyz, Howard Shuman, Tomas Vaisar, Lev Becker
Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic "macrophage-sterol-responsive-network" (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor (Ifngr1−/−) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and 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. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis.

Graphical abstract

Teaser

Obesity and insulin resistance are major risk factors for cardiovascular disease, but the underlying mechanisms are poorly understood. Reardon et al. show that obesity and insulin resistance induce an IFNγ-macrophage pathway that exacerbates foam cell formation and aortic lesion size in atherosclerotic mice.


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