Obesity is associated with a state of chronic, low-grade inflammation and alterations in fat mass are associated with changes in energy intake and storage, insulin sensitivity, and metabolism. However the molecular pathways underlying a link between chronic inflammation and insulin resistance are unknown.
In the 15 December issue of the Journal of Clinical Investigation studies from two independent US-based research groups, one at the Novartis Institutes for Biomedical Research in Massachusetts and the other at the Naomi Berrie Diabetes Center at Columbia University, New York, report that obese fatty tissue is characterised by the infiltration of macrophages and that these macrophages are an important source of inflammation in this tissue.
Both studies used large-scale gene expression analysis and histological evidence to compare the differences in gene expression in multiple tissues of both lean mice and mice of varying degrees of obesity. They found that the largest class of genes significantly regulated in obesity consists of macrophage and inflammatory genes in fatty tissue.
Anthony Ferrante and colleagues provide evidence that macrophage infiltration of adipose tissue is characteristic of human obesity, by demonstrating that body mass index and average fat cell size were significant predictors of macrophage accumulation in adipose tissue.
Hong Chen and colleagues demonstrated that the upregulation of many inflammation and macrophage-specific genes precedes a dramatic increase in circulating insulin levels and treatment with an insulin-sensitizing drug triggered down regulation of these genes. The data suggests that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.
In an accompanying commentary, Kathryn Wellen and Gökhan Hotamisligil from the Harvard School of Public Health discuss the inflammation of obese adipose tissue. While it remains to be shown how the inflammatory response in fatty tissue causes insulin resistance, these two studies prompt consideration of new models of the molecular changes that occur in fatty tissue in obesity in which macrophages play a major role.