The Role of Substrate Metabolism and Macrophage Activation in Obesity

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DESCRIPTION (provided by applicant): The World Health Organization estimates 500 million adults and as many as 43 million children under the age of 5 are obese underscoring the fact that obesity and its related diseases, including insulin resistance and diabetes, remains a significant global public health problem. Research conducted over the past decade has increasingly linked obesity and inflammation; pro-inflammatory, classically activated M1 macrophage cells of the innate immune system infiltrate adipose tissue at the onset of weight gain contributing to the inflammatory state of fat, ultimately resulting in systemic insulin resistance, while alternatively activated, anti-inflammatory M2 macrophages safeguard insulin sensitivity in metabolic tissues. The mechanisms controlling macrophage subtype remain unclear and it is possible the type of energy substrates available to macrophages in the tissue microenvironment, or the ability of these cells to utilize specific substrates for fuel, may be one mechanism by which macrophage phenotype is modulated. Aim 1 of this proposal will explore how restricting fuel substrate availability affects macrophage subtype (i.e. pro- versus anti-inflammatory) through the use of a macrophage-specific glucose transporter 1 knockout mouse (Glut1 M�-/-) and a high-fat feeding model of diet-induced obesity. Metabolic phenotyping, including body weight and composition, food intake and activity, systemic insulin sensitivity and glucose tolerance, and energy expenditure will be performed on lean and obese Glut1 M�-/- and wildtype littermate controls. The degree of macrophage infiltration in epididymal white adipose tissue (eWAT), as well as macrophage subtype and modifications to the eWAT insulin signaling pathway, will be determined using a combination of histologic, gene and protein expression analyses. Lastly, the effect of macrophage phenotype on the eWAT microenvironment in total will be characterized through the use of genomic microarray analysis and metabolomic profiling. Obesity is considered an immune-suppressive state and the Centers for Disease Control and Prevention now recognize obesity as an independent risk factor for increased influenza morbidity and mortality. Aim 2 of this proposal will explore the relationship among obesity, macrophage phenotype and influenza infection and their joint influence over flu infection severity. The Glut1M�-/- / diet-induced obesity model will be used as in Aim 1, with the addition o an influenza infection. Overall survival, lung pathology, viral clearance and immune cell population characterization will be completed. This project will afford an opportunity to work closely with, and be mentored by, a team of highly respected researchers in the public health fields of obesity and infectious disease. Completion of this research project will culminate in mastery of skills such as conducting controlled animal feeding studies, metabolic phenotyping, immune system characterization, and bioinformatic analyses of large genomic and metabolomics data sets, manuscript writing, data presentation, granstmanship and research project management.