Obesity induces an inflammatory response that has been implicated in the development of medically important complications, including atherosclerosis, insulin resistance, non-alcoholic fatty liver disease and cancer. Studies supported by this grant have revealed a previously unrecognized component of obesity- induced inflammation: adipose tissue macrophages (ATMs). Our work has demonstrated that ATMs accumulate in adipose tissue in proportion to adiposity in both rodents and humans. We have also shown that ATMs are responsible for elaborating proinflammatory, pro-coagulant and acute phase proteins implicated in obesity-induced complications. Through use of mice deficient in a chemoattractant receptor, we have decreased macrophage content in adipose tissue and concomitantly improved the metabolic profile of obese mice. Studies stimulated by our findings have demonstrated that ATM content in humans is tightly correlated with adiposity, insulin sensitivity and powerfully decreased by thiazolidiniones. A more detailed characterization of the process that regulates macrophage accumulation and activation in adipose tissue will provide important insights into the pathophysiology of obesity and its complications, and also provide candidate therapeutic targets. Two basic hypotheses motivate the experiments described in this application: (A) In obesity macrophage accumulation in adipose tissue is a multi-step process that consists of three steps: recruitment, maturation/differentiation and activation. (B) Activated adipose tissue macrophages contribute to the adverse local and systemic inflammatory effects of obesity . In other biological settings the recruitment, differentiation and activation of macrophages have been well characterized.
Our specific aims are: (1) To characterize obesity-induced recruitment of monocytes to adipose tissue. (2) To determine whether M-CSF/CSF-1 regulates adipose tissue macrophage differentiation. (3) To determine whether obesity-induced adipose tissue inflammation is dependent upon macrophage NF-kB activation.
The specific aims of the current application are designed to identify mechanisms involved in eacg step of macrophage accumulation, and measure the contribution of each to the local and systemic inflammation induced by obesity. In this proposal we have taken advantage of the rich literature that describes macrophage physiology and our preliminary data to propose molecular mechanisms required for recruitment, differentiation and activation of ATMs. Achieving these specific aims of this proposal will identify critical processes and molecules required for ATM accumulation. Success also will provide important insights into adipose tissue physiology, and by identifying the molecular mechanisms that regulate macrophage accumulation and activation in adipose tissue, identify potential novel strategies to reduce obesity-induced inflammation and its attendant complications. ? ? ?
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