PMID- 23620818
OWN - NLM
STAT- MEDLINE
DCOM- 20131111
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 4
DP  - 2013
TI  - PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, 
      insulin-resistant mice depends on adiponectin-induced Irak3 expression.
PG  - e62253
LID - 10.1371/journal.pone.0062253 [doi]
LID - e62253
AB  - 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 PPARalpha agonist (fenofibrate) and 
      a PPARgamma 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 Ppargamma 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 NFkappaB 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.
FAU - Hulsmans, Maarten
AU  - Hulsmans M
AD  - Atherosclerosis and Metabolism Unit, Department of Cardiovascular Sciences, KU 
      Leuven, Leuven, Belgium.
FAU - Geeraert, Benjamine
AU  - Geeraert B
FAU - Arnould, Thierry
AU  - Arnould T
FAU - Tsatsanis, Christos
AU  - Tsatsanis C
FAU - Holvoet, Paul
AU  - Holvoet P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adiponectin)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Insulin)
RN  - 0 (Leptin)
RN  - 0 (PPAR alpha)
RN  - 0 (PPAR gamma)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
RN  - U202363UOS (Fenofibrate)
SB  - IM
MH  - Adipocytes/drug effects/metabolism/pathology
MH  - Adiponectin/blood/*metabolism
MH  - Animals
MH  - Chemokine CCL2/*metabolism
MH  - Diet, High-Fat
MH  - Fenofibrate/pharmacology/therapeutic use
MH  - Inflammation/blood/drug therapy/pathology
MH  - Insulin/pharmacology
MH  - *Insulin Resistance
MH  - Interleukin-1 Receptor-Associated Kinases/*metabolism
MH  - Leptin/blood
MH  - Macrophages/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Obesity/blood/drug therapy/*metabolism/physiopathology
MH  - PPAR alpha/agonists/metabolism
MH  - PPAR gamma/agonists/metabolism
MH  - Peroxisome Proliferator-Activated Receptors/*agonists/metabolism
MH  - Plaque, Atherosclerotic/drug therapy/*metabolism/pathology
MH  - Rosiglitazone
MH  - Thiazolidinediones/pharmacology/therapeutic use
PMC - PMC3631170
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/04/27 06:00
MHDA- 2013/11/12 06:00
PMCR- 2013/04/19
CRDT- 2013/04/27 06:00
PHST- 2012/11/20 00:00 [received]
PHST- 2013/03/19 00:00 [accepted]
PHST- 2013/04/27 06:00 [entrez]
PHST- 2013/04/27 06:00 [pubmed]
PHST- 2013/11/12 06:00 [medline]
PHST- 2013/04/19 00:00 [pmc-release]
AID - PONE-D-12-36581 [pii]
AID - 10.1371/journal.pone.0062253 [doi]
PST - epublish
SO  - PLoS One. 2013 Apr 19;8(4):e62253. doi: 10.1371/journal.pone.0062253. Print 2013.