Molecular and genetic studies examining the inflammatory consequences of obesity

Obesity is associated with a pro-inflammatory state that confers increased risk for developing type 2 diabetes mellitus and cardiovascular disease and that may reflect increased activation of the innate immune system.; We performed gene expression profiling of adipose tissue from several models of murine obesity. Analysis of this dataset led to the discovery that adipose tissue becomes heavily infiltrated by macrophages---a major effector cell of the innate immune system---in direct proportion to degree of adiposity. These adipose tissue macrophages may play an important role in regulating the pro-inflammatory state associated with obesity.; A critical step in the progression of the innate immune response involves the secretion of chemokines which recruit effector cells to sites of inflammation. Several chemokine ligands of the chemokine receptor, CCR2, are overproduced in adipose tissue of obese compared to lean individuals. We examined the metabolic and inflammatory phenotypes of lean and obese mice genetically deficient in CCR2. These animals had less macrophage infiltration of adipose tissue when made obese and were partially protected from the development of insulin resistance. However, other pro-inflammatory responses associated with obesity---including increased circulating cytokine levels and overexpression of TNF-alpha in adipose tissue---were not CCR2 dependent.; Another critical step in the progression of the innate immune response is the activation of pattern recognition receptors in the toll-like receptor (TLR) family. The adaptor molecule, MYD88, directly couples to activated TLRs where it plays a central role in TLR signaling. We used bone marrow transplantation into wild type mice to create chimeric mice with either wild type or Myd88-deficient bone marrow cells. Compared to controls, the chimeric mice with Myd88-deficient bone marrow became equally obese on a high fat diet, but had reduced circulating levels of inflammatory biomarkers; decreased expression of pro-inflammatory molecules in liver and muscle tissue; and improved insulin sensitivity. However, these changes occurred in the absence of any change in the expression of pro-inflammatory genes in adipose tissue.; These studies have identified two molecular pathways leading to increased inflammatory activity and insulin resistance associated with obesity; a CCR2-dependent process that mediates recruitment of macrophages to adipose tissue, and a MYD88-dependent systemic inflammatory process.