Effect of peroxisome proliferator-activated receptor-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue.
OBJECTIVE
This study was designed to examine the effect of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands on the inflammatory changes induced by the interaction between adipocytes and macrophages in obese adipose tissue.


METHODS
PPAR-alpha ligands (Wy-14,643 and fenofibrate) were added to 3T3-L1 adipocytes, RAW264 macrophages, or co-culture of 3T3-L1 adipocytes and RAW264 macrophages in vitro, and monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) mRNA expression and secretion were examined. PPAR-alpha ligands were administered to genetically obese ob/ob mice for 2 weeks. Moreover, the effect of PPAR-alpha ligands was also evaluated in the adipose tissue explants and peritoneal macrophages obtained from PPAR-alpha-deficient mice.


RESULTS
In the co-culture of 3T3-L1 adipocytes and RAW264 macrophages, PPAR-alpha ligands reduced MCP-1 and TNF-alpha mRNA expression and secretion in vitro relative to vehicle-treated group. The anti-inflammatory effect of Wy-14,643 was observed in adipocytes treated with macrophage-conditioned media or mouse recombinant TNF-alpha and in macrophages treated with adipocyte-conditioned media or palmitate. Systemic administration of PPAR-alpha ligands inhibited the inflammatory changes in adipose tissue from ob/ob mice. Wy-14,643 also exerted an anti-inflammatory effect in the adipose tissue explants but not in peritoneal macrophages obtained from PPAR-alpha-deficient mice.


CONCLUSIONS
This study provides evidence for the anti-inflammatory effect of PPAR-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue, thereby improving the dysregulation of adipocytokine production and obesity-related metabolic syndrome.
Toyoda
Takuya
T
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Kamei
Yasutomi
Y
Kato
Hirotsugu
H
Sugita
Satoshi
S
Takeya
Motohiro
M
Suganami
Takayoshi
T
Ogawa
Yoshihiro
Y
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008024:Ligands; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C006253:pirinixic acid; D011345:Fenofibrate