Obesity is an independent risk factor for type 2 diabetes mellitus, cardiovascular disease, non-alcoholic steatohepatitis, stroke and certain cancers. A critical factor in obesity disorders is adipose tissue (AT) inflammation, which is caused in large part by macrophages that infiltrate AT. Neither the precipitating event(s) nor function(s) of macrophage infiltration into AT are known. Our data demonstrate that >90% of macrophages in AT of obese mice and humans are localized to sites of adipocyte death, where they surround and scavenge remnant lipid droplets and express cytokines (TNF-alpha, IL-6) that can dysregulate adipocyte insulin signaling, PPAR-gamma-dependent gene expression and lipolysis. Notably, adipocyte death increases dramatically with obesity and is temporally correlated with the onset and development of insulin resistance in mice. These data suggest a model of obesity-associated AT inflammation in which obesity promotes adipocyte death, adipocyte death recruits and activates macrophages, and macrophage-derived pro-inflammatory mediators promote additional adipocyte death and inflammation. Studies will test this model in mice, using morphological, and cell biological gene expression and metabolic approaches.
In Aim 1 we will use a transgenic mouse model of caspase 8-induced adipocyte apoptosis to determine the contribution of adipocyte death to AT inflammation and insulin resistance in the presence and absence of obesity-related factors.
In Aim 2 we use a knockout mouse that is deficient in macrophage inflammatory (NF-?B) dependent gene expression to determine the contribution of macrophage pro-inflammatory mediators to adipocyte dysregulation and death.
In Aim 3 we use transgenic mouse models of adipocyte hypertrophy and hyperplasia, respectively to test the hypothesis that obesity-associated adipocyte death and macrophage infiltration of AT occur preferentially in AT depots that expand primarily by hypertrophy (i.e., epididymal).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Abraham, Kristin M
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Tufts University
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