Aged insulin resistant macrophages reveal dysregulated cholesterol biosynthesis, a pro-inflammatory profile and reduced foam cell formation capacity

Abstract

Insulin resistance is the central defining feature of type 2 diabetes and an independent risk factor for the development of atherosclerosis. In addition, aging is a major risk factor in the development of insulin resistance and cardiovascular disease. Macrophages play a pivotal roles the the developments of diabetes and atherosclerosis and express insulin receptors. Despite their relevance however, the effect of insulin and insulin resistance on macrophages regarding their inflammatory status, foam cell formation capacity and affect on atherosclerosis are unclear. By taking advantage of a mouse model that recapitulates the effects of chronic PI3K pathway hyperstimulation in macrophages through SHIP2 knock-down, we show that insulin resistance in aged macrophages promotes a proinflammatory phenotype while modulating the cholesterol biosynthesis pathway. These altered characteristics may contribute to the development of chronic inflammatory disease frequently observed with age. Moreover, aged insulin-resistant proinflammatory macrophages display an altered response to acute inflammatory stimulus and reduced foam cell formation capacity. Our work also highlights for the first time, the complex and contrasting immunomodulatory effects of insulin on macrophages in aged mice.\n\nSignificanceO_LIFirst study to explore the effects of macrophage insulin resistance in aged cells.\nC_LIO_LIInsulin resistance in aged macrophages results in the reprogramming of the transcriptome with more than 4000 genes being differentially regulated.\nC_LIO_LIInsulin resistance in aged macrophages results in upregulation of IFN signalling pathway, cholesterol biosynthesis pathway and inflammasome gene expression.\nC_LIO_LIInsulin directly regulates macrophage cholesterol biosynthesis, IFN and inflammasome gene expression in a time- and dose-dependent manner.\nC_LIO_LIInsulin resistant aged macrophages exhibit reduced capacity to become foam cells.\nC_LI