Endocrine Abstracts

Background: Insulin resistance and ageing are risk factors for the development of type 2 diabetes and atherosclerosis. Insulin signalling in macrophages affects their inflammatory responses and foam cell formation capacity, yet the mechanisms linking these remain unclear. Recent evidence has emerged linking macrophage lipid metabolism and inflammatory response such as an interferon-cholesterol pathway flux axis. Insulin has been shown to directly regulate cholesterol biosynthesis in liver and brain. SHIP2 is a negative regulator of insulin mediated PI(3)K signalling pathway which is affected in insulin resistant patients.

Methods: Hematopoietic SHIP2 knock-down mice (h-SHIP2KD) were aged for 50 weeks. Bone marrow derived macrophages (BMDM) were compared to their aged cre expressing control litter mates.

Results: BMDM from aged h-SHIP2KD mice were shown to be insulin resistant through lack of acute phosphoAkt-S473 induction by insulin. Transcriptome array profiling revealed the differential expression of more than 600 genes by more than 2-fold, FDR-adj P value <0.05). Hallmark pathway analysis showed interferon immune responses were the top regulated pathways. A selection of interferon responsive genes were confirmed by RT-qPCR in separate experiments. Further interrogation of the array data revealed significant up-regulation of genes involved in cholesterol biosynthesis in the aged insulin resistant h-SHIP2KD BMDM which were also confirmed by qPCR, and Oil red O staining revealed increased lipid content in the aged insulin resistant h-SHIP2KD cells. Furthermore, when challenged acutely with insulin, young insulin-responsive BMDM also show significant changes in cholesterol biosynthesis and interferon gene expression. Oil red O staining after incubation with acetylated LDL revealed aged h-SHIP2KD BMDM showed significant resistance to foam cell formation when compared to controls.

Conclusion: We propose a novel unifying mechanism, in which insulin affects macrophage inflammatory responses through insulin’s effect on macrophage cholesterol metabolism.