fr-167653 and Obesity

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.

Topics: Activating Transcription Factor 2; Adipocytes, White; Adipogenesis; Animals; Anti-Obesity Agents; Bone Morphogenetic Protein 2; Cyclic AMP Response Element-Binding Protein A; Female; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Obesity; p38 Mitogen-Activated Protein Kinases; PPAR gamma; Protein Kinase Inhibitors; Pyrazoles; Pyridines; RNA, Messenger; Tumor Necrosis Factor-alpha