The Role of Macrophage Scavenger Receptor 1 in Type 2 Diabetes

摘要

ABSTRACT Type 2 Diabetes (T2D) is a metabolic disease characterized by insulin resistance, hyperglycemia, and adipose tissue dysfunction that disproportionately affects the African American population. Obesity is the number one modifiable risk factor for T2D, but the mechanisms that link the two remain incompletely understood. Previous research into this link revealed that obesity induces a chronic inflammatory state accompanied by both an increase in adipose tissue macrophages and inflammatory cytokines. Adipose tissue macrophages (ATMs) contribute to adipocyte dysfunction and systemic insulin resistance. Many gaps remain in our understanding of how ATM function is regulated by obesity and contributes to adipocyte dysfunction. The goal of this proposal is to complete a research plan centered on a novel mechanism regulating ATM function relevant to T2D, while enhancing pre-doctoral training in immunometabolism and translational research. The central hypothesis of this proposal is that macrophage scavenger receptor 1 (MSR1) is required to promote insulin resistance and adipose tissue inflammation via the regulation of ATM proliferation. MSR1 is a multifunctional macrophage surface receptor that is associated with T2D in humans but has also been suggested to have protective effects on insulin resistance in mice. The premise for our studies is based on preliminary data in the lab suggesting altered ATM proliferation in Msr1-/- mice. The proposed research plan will address the following aims: 1) To evaluate the requirement for MSR1 maintaining insulin sensitivity in obesity, 2) To evaluate if MSR1 is required for ATM proliferation, 3) To assess MSR1 expression in human adipose tissue and evaluate African American adipose tissue transcriptomics in T2D. The proposed experimental approach will utilize obese mouse models and human adipose tissue from obese patients combined with advanced techniques for cell sorting and cellular metabolism. The research and training plan will be overseen by sponsors and mentors with expertise in adipose tissue biology, immunometabolism, macrophage function, and human subjects research.