The increasing prevalence of obesity drives a critical need to understand the link between obesity and disease. Impairment in adipose tissue nutrient storage in obesity promotes ectopic lipid deposition and elevates the risk for insulin resistance and cardiovascular disease. Adipose tissue macrophages (ATMs) have been identified as critical regulators of adipose tissue function and drivers of obesity-related metabolic dysfunction However, there are major gaps in our understanding of the mechanisms that regulate ATM quantity, the functional differences between discrete ATM subtypes, and how ATM subtypes contribute to human disease. Recent data suggest that proliferation and internal lipid storage are important features of ATMs but how or if these are linked is unknown. The objective of this application is to determine the mechanisms contributing to the generation of lipid-laden ATMs in obesity and their relationship to human metabolic dysfunction. Our central hypothesis is that free fatty acids (FFA) induce proliferation of resident lipid-laden ATMs that contribute to metabolic disease. This will be assessed by completing two research aims using complementary studies in mouse and human adipose tissue samples: 1) To determine the mechanisms governing expansion of the resident lipid-laden ATM pool in obesity. Mouse models of obesity will be used to evaluate a time course of proliferation of lipid-laden ATMs. FFA-induced ATM proliferation will be examined in vitro. Genetic lineage tracing in mouse obesity models will examine the hypothesis that lipid-laden ATMs expand through proliferation of a resident pool. 2) To determine the relationship between proliferating lipid-laden ATMs and metabolic disease in obese humans. A cross-sectional study in obese patients undergoing bariatric surgery will be performed to examine the hypothesis that proliferating lipid-laden ATMs in human visceral adipose tissue correlate with insulin resistance. Completing our aims will significantly impact our understanding of the mechanisms by which ATMs are regulated and contribute to metabolic disease. This proposal will address several gaps in the field of immunometabolism, including gaps between mouse and human biology and in understanding which ATM subsets are most important in adipose tissue dysfunction. Furthermore, identifying the resident or non-resident origin of ATM subtypes associated with metabolic dysfunction would be a significant advance in informing targeting strategies to break the link between metabolic dysfunction and disease. Completion of the aims and training goals, performed under the supervision of an integrated team of basic and clinical mentors, will significantly accelerate career and skills development of the postdoctoral trainee in the pursuit of an independent career with translational focus in the immunometabolism field.
Obesity is associated with health risks such as diabetes and cardiovascular disease, but the mechanisms contributing to obesity-related disease are poorly understood. Inflammation and activated immune cells within fat tissue have been identified as links between obesity and disease. In particular, the balance of different types of macrophages in fat has been associated with metabolic disease. Identifying which macrophage types are involved in obesity-related risk could provide novel targets for therapeutic intervention as well a key new indicators for identifying human populations that are the most at-risk for metabolic and cardiovascular disease.
