Abstract
Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate) and a PPARγ agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO) were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3) and decreased monocyte chemoattractant protein-1 (Mcp1) expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM), we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3−/− BMDM) resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3−/− BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.
Highlights
Low-grade chronic inflammation is associated with obesity and obesity-induced metabolic disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis [1,2]
We showed that decreased expression of interleukin-1 receptor-associated kinase-3 (IRAK3) in monocytes of obese patients is associated with a high prevalence of metabolic syndrome; weight loss results in an increase in IRAK3 that is associated with decreased systemic inflammation [10]
Because defective leptin signaling was found to modulate inflammation and atherosclerosis [18], we studied the relation between low adiponectin (Adipoq) and interleukin-1 receptor-associated kinase-3 (Irak3) expression in aortic extracts of high-fat and insulin resistant LDL-receptor deficient mice characterized by high plasma leptin levels
Summary
Low-grade chronic inflammation is associated with obesity and obesity-induced metabolic disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis [1,2]. The recruitment of monocytes and differentiation and polarization to classically activated pro-inflammatory M1 macrophages instead of anti-inflammatory M2 macrophages, have been causally linked to the development of adipose tissue dysfunction, the metabolic syndrome and atherosclerosis [3]. It is recognized that maladaptive production of various adipocytokines (e.g. adiponectin, resistin, visfatin, and leptin) and pro-inflammatory cytokines, such as tumor necrosis factor-a (TNFa) and interleukin (IL)-6, are implicated in the development of obesityrelated systemic inflammation and insulin resistance. The blood levels of adiponectin are significantly lower in obese individuals and have been associated with metabolic inflammation, insulin resistance and the development of cardiovascular disease [5]. We showed that decreased expression of IRAK3 in monocytes of obese patients is associated with a high prevalence of metabolic syndrome; weight loss results in an increase in IRAK3 that is associated with decreased systemic inflammation [10]
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