Abstract 594: Macrophage Proteomics Identifies Mechanistic Links Between Type 2 Diabetes and Atherosclerosis
Obesity and Type 2 Diabetes (T2Ds) are associated with increased risk of atherosclerosis and CHD. However, the mechanism(s) linking these diseases are incompletely understood. Macrophages play essential roles in the pathogenesis of both disorders, suggesting that changes in macrophage biology link obesity/T2D and atherosclerosis. We previously showed that the atherogenic actions of cholesterol-loaded macrophages (foam cells) are an emergent property of a dysregulated sterol responsive protein network secreted by macrophages (MSRN). Thus, we hypothesized that obesity/T2Ds may impact atherogenesis by similarly disrupting the MSRN.
To test this hypothesis, we isolated peritoneal macrophages (PMΦ) from C57BL/6 mice fed a chow or obesogenic diet and interrogated their secreted proteomes using mass spectrometry. Based on stringent statistical analysis (FDR<5%), we identified 36 proteins that were differentially expressed in media conditioned by macrophages from obese relative to lean mice. Unsupervised gene set enrichment analysis demonstrated that obesity-induced changes to the PMΦ proteome significantly targeted the MSRN. Importantly, this phenomenon could not be explained by cholesterol accumulation or inflammation, since PMΦ’s from obese mice did not accumulate cholesterol and pro-inflammatory cytokine expression was not induced in PMΦ’s from obese or atherogenic mice.
Our previous studies showed that treating hypercholesterolemic Ldlr-/- mice with TZD (insulin sensitizer) could normalize MSRN protein expression in vivo, suggesting that insulin resistance is a key regulator of the network. To test this hypothesis, we placed C57BL/6 mice on an obesogenic diet for 7 weeks and treated the mice with TZD for 2 weeks. TZD therapy had no effect on body weight, but normalized fasting glucose levels. Moreover, PMΦ’s isolated from TZD-treated mice, demonstrated normalized protein expression patterns. Collectively, our studies suggest that insulin resistance in T2Ds reproduces macrophage protein dysfunction observed in atherogenic models, and provides a plausible mechanism by which T2Ds may act to increase risk of atherosclerosis.
Author Disclosures: B. Coats: None. K. Schoenfelt: None. L. Becker: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.