Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.
OBJECTIVE
We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity.


METHODS
Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated.


RESULTS
Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of kappaB kinase-beta (IKKbeta) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3.


CONCLUSIONS
Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKbeta and JNK pathways.
Jiao
Ping
P
Hallett Center for Diabetes and Endocrinology, Brown Medical School, Providence, Rhode Island, USA.
Chen
Qiu
Q
Shah
Suketu
S
Du
Jing
J
Tao
Bo
B
Tzameli
Iphigenia
I
Yan
Weiqun
W
Xu
Haiyan
H
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D005230:Fatty Acids, Nonesterified; D018945:Monocyte Chemoattractant Proteins; D016328:NF-kappa B; C468928:Spag9 protein, mouse