title: PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression.
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.
authors.affiliation: Atherosclerosis and Metabolism Unit, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hulsmans
authors.forename: Benjamine
authors.initials: B
authors.lastname: Geeraert
authors.forename: Thierry
authors.initials: T
authors.lastname: Arnould
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052242:Adiponectin / Q000097:blood / Q000378:metabolism*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D059305:Diet, High-Fat; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D052242:Adiponectin; D018932:Chemokine CCL2; D007328:Insulin; D020738:Leptin; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D053592:Interleukin-1 Receptor-Associated Kinases; D011345:Fenofibrate