An investigation of the immunometabolic interactions of obesity

Human monocytes are classified as classical, intermediate and non-classical according to their surface expression of CD14 and CD16. They also represent precursors to atherogenic foam cells and macrophages in metabolically adverse crown-like structures. Monocyte distribution, phenotype and function were investigated in obese individuals with and without type 2 diabetes in relation to clinical parameters of metabolic and cardiovascular risk. Peripheral monocytes obtained from obese and non-obese subjects were enumerated and their phenotype investigated using flow cytometry and q-RT-PCR. Multivariate analyses were performed against validated clinical markers of cardiovascular and metabolic risk. When compared to their non-obese counterparts, obese individuals demonstrated decreased total and classical monocyte numbers with proportionately increased intermediate monocytes and unchanged non-classical monocytes. Surface staining of intermediate monocytes for HLA-DR identified two distinct subpopulations with mid (DR mid) and high (DR hi) level expression respectively. Expansion of the intermediate subset of monocytes in obese individuals occurred specifically within the DRmid subpopulation and this correlated with key indices of lipid metabolism and glycemia. DRmid intermediate monocytes displayed higher surface expression of pro-inflammatory and lipid receptors and higher uptake of acetylated-LDL. A distinct subpopulation of intermediate monocytes sharing phenotypic features with atherogenic foam cells and macrophages in crown-like structures is expanded in the blood of obese individuals with and without type 2 diabetes. Direct interactions between modified lipoproteins and circulating monocyte subpopulations may represent an early pathogenic driver of obesity-associated atherosclerosis and adipose tissue inflammation