University of California, San Francisco (UCSF)

Regulation of Insulin Sensitivity by Macrophage-Specific PGC-1β

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By promoting a state of chronic low-grade inflammation, obesity exacerbates many health problems, including insulin resistance and type 2 diabetes mellitus (T2DM). Obese individuals have elevated levels of pro-inflammatory cytokines (many of which are secreted by “classically activated” macrophages) known to cause insulin resistance. This suggests that down regulation of macrophage-mediated inflammation might lead to improvement in insulin action. Our preliminary data show that polarization of macrophages to the anti-inflammatory “alternative state” of activation protects transgenic mice from obesity-induced glucose intolerance, whereas impairment in alternative macrophage activation leads to the worsening of metabolic syndrome. Therefore, it is pivotal to characterize factor(s) affecting macrophage’s “activation state” and the mechanisms by which these factors determine either susceptibility to, or protection against, development of T2DM.

Towards this goal, our laboratory utilizes mouse models of disease and molecular biology tools to study the function of the mitochondrial energy regulator factor (PGC1β) and the lipid-sensors (PPARγ and PPARδ) in macrophage action. Overall, our findings provide important new information that polarization of resident and recruited tissue macrophages to the alternative state can enhance insulin sensitivity, representing a new signaling axis that can potentially be exploited to treat insulin resistance and T2DM.