The role of ATF-2 family transcription factors in adipocyte differentiation: antiobesity effects of p38 inhibitors.
ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor gamma2 (PPARgamma2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-alpha) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment.
Maekawa
Toshio
T
RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan. maekawa@rtc.riken.jp
Jin
Wanzhu
W
Ishii
Shunsuke
S
D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000502:physiology*; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D051699:Cyclic AMP Response Element-Binding Protein A / Q000235:genetics / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009765:Obesity / Q000201:enzymology*; D047495:PPAR gamma / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051698:Activating Transcription Factor 2; D019440:Anti-Obesity Agents; C497106:Atf2 protein, mouse; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D051699:Cyclic AMP Response Element-Binding Protein A; C104334:FR 167653; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases