The role of circulating meta-inflammatory monocytes in adolescent insulin resistance

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ABSTRACT Adults with obesity have increased myeloid inflammatory responses that associate with cardiovascular and metabolic disease. There are several gaps, though, in our current understanding of metabolic inflammation (meta-inflammation) including our understanding of initiating changes in myelopoiesis and regulated changes in myeloid cells. It is clear that some individuals develop a meta-inflammatory response placing them at higher risk for metabolic impairment while others are protected. While it is clinically important to identify adolescents at risk for future disease, we do not understand how to use meta-inflammatory markers to assess disease risk. Our previous human and mouse studies demonstrate that individuals who expand inflammatory monocytes in response to obesogenic diets are at greatest risk for metabolic disease. Based on the ability of these monocytes to generate an inflammatory response, traffic to tissues and differentiate into inflammatory tissue macrophages promoting insulin resistance, we are terming them meta-inflammatory monocytes (MiMo). Given that animal models and clinical studies have demonstrated that myeloid inflammation with circulating cytokines, enhanced circulating myeloid cells and tissue inflammation are linked with insulin resistance it is critical to understand if these same mechanisms exist in adolescents and can differentiate who is at risk for future metabolic disease. This proposal is based on the scientific premise that a diet high in saturated fatty acids (SFA) leads to myeloid leukocyte activation with expansion of myeloid progenitors, Ly6chi blood monocytes, and pro-inflammatory tissue macrophages leading to tissue dysfunction in animal studies. We propose the central hypothesis that adolescents at risk for metabolic disease have an increase in MiMos and enhanced MiMo recruitment, cytokine secretion and macrophage polarization leading to insulin resistance. We will evaluate this hypothesis in three aims: Aim 1) To define the monocyte transcriptomic signatures associated with metabolic disease in adolescents. Aim 2) To determine high risk and low risk monocyte phenotypes produced in adolescents with metabolic impairment. Aim 3) To assess meta-inflammatory monocyte activation and metabolism in response to dietary fatty acid stimulation. This proposal is innovative in the modeling and translational approach which is of high clinical significance. While the role of inflammation and metabolic disease has been studied over the last few decades little is known about this association in adolescents. This project will close the critical gap in translating pre-clinical studies on meta-inflammatory monocytes (MiMos) to adolescents. It will also investigate the mechanisms of disease risk through identification of detrimental monocyte phenotypes and the role of dietary fats in driving MiMo activation. These findings will lead to both biomarkers for prediction and pathways for intervention in pediatric metabolic disease.