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

Abstract

SUMMARY 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.

Triglyceride glucose index is an independent predictor for the progression of coronary artery calcification in the absence of heavy coronary artery calcification at baseline

“…The mechanism underlying the relationship of the TyG index with atherosclerosis is unclear. However, previous studies revealed the pivotal role of IR in atherosclerosis progression via promoting apoptosis of macrophages, endothelial cells, and vascular smooth muscle cells [36][37][38]. Recently, data from Coronary Artery Risk Development in Young Adults (CARDIA) study revealed that transitions in metabolic risk occurred early in life and metabolic dysfunction is related to subclinical cardiovascular phenotypes including CAC and myocardial hypertrophy and dysfunction [39].…”

STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

“…Obesity and insulin resistance increase IFN γ production 39 and IFN γ -mediated activation of the transcription factor STAT1 blocks adipocyte differentiation 15,21,29,38 . We extend these findings with genetic and RNA interference studies in vitro that demonstrate STAT1 depletion increases human and mouse adipocyte differentiation.…”

“…Indeed, complete elimination of IFN γ activity improves insulin sensitivity in obese mice. Although whole body IFN γ gR1 deletion exposes impacts on immunity across multiple endocrine tissues 17,39,41 , IFN γ gR1− /− adipocytes resist the detrimental effects of IFN γ on metabolism and nominate cell autonomous functions that restrict WAT expandability in obesity.…”

“…Pro-inflammatory cytokines inhibit insulin signaling and mitochondrial function in adipocytes. Also, numerous studies established strong correlations between pro-inflammatory cytokines, like TNF α 48,49 and IFN γ 39 and energy balance defects in adipose tissue. However, TNF α inhibitors and other or broad anti-inflammatory strategies that impact STAT1 or STAT3 activity lack clinical efficacy in the treatment of obesity 50–53 .…”

Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine‐N‐Oxide Reduction and Mechanism of Microbiota Regulation

“…A. muciniphila has been recently reported as a beneficial bacterium that reduces gut barrier disruption and insulin resistance. Also, pterostilbene has therapeutic potential by modulating inflammatory response and attenuates vascular disease …”