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

BioRxiv : the Preprint Server for Biology
Gwladys ChabrierMatthew C Gage

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 effe...Continue Reading

Related Concepts

Aging
Atherosclerosis
Cardiovascular Diseases
Diabetes
Diabetes Mellitus, Non-Insulin-Dependent
Foam Cells
Insulin
Insulin Resistance
Macrophage
Laboratory mice

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