The role of ATF-2 family transcription factors in adipocyte differentiation: antiobesity effects of p38 inhibitors

Mol Cell Biol. 2010 Feb;30(3):613-25. doi: 10.1128/MCB.00685-09. Epub 2009 Nov 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / genetics
  • Activating Transcription Factor 2 / physiology*
  • Adipocytes, White / cytology
  • Adipocytes, White / drug effects
  • Adipocytes, White / enzymology
  • Adipogenesis / genetics*
  • Animals
  • Anti-Obesity Agents / pharmacology*
  • Bone Morphogenetic Protein 2 / metabolism
  • Cyclic AMP Response Element-Binding Protein A / genetics
  • Cyclic AMP Response Element-Binding Protein A / physiology*
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Obesity / enzymology*
  • PPAR gamma / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Activating Transcription Factor 2
  • Anti-Obesity Agents
  • Atf2 protein, mouse
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Cyclic AMP Response Element-Binding Protein A
  • FR 167653
  • PPAR gamma
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases