http / / cjbmb. bjmu. edu. cn Chinese Journal of Biochemistry and Molecular Biology . Hh Hedgehog Signaling Pathway and Adipocyte Development

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1 ISSN CN / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology ~ 10 Hedgehog * TGFβ Wnt FGF Hedgehog Hh Hh Hh Hh Hh Hedgehog Q54 Hedgehog Signaling Pathway and Adipocyte Development CHEN Jing-Wen TANG Qi-Qun * Key Laboratory of Molecular Medicine Ministry of Education Department of Biochemistry and Molecular Biology Fudan University Shanghai Medical College Shanghai China Abstract The hedgehog Hh signaling pathway is conserved from flies to humans and plays important roles in the processes of embryonic development of many kinds of organs similar to the TGFβ Wnt FGF pathways The development of mature adipocytes undergoes two distinct stages the commitment of pluripotent stem cells to preadipocytes and the terminal differentiation preadipocytes into mature adipocytes Recently the Hh signaling pathway has been found to inhibit adipogenesis In this review we focus on the discussion of the inhibitory role of the Hh signaling pathway and its regulation in the stages of adipocyte development Finally the potential of hedgehog as a pharmacological target to treat obesity and obesity-related diseases was evaluated Key words hedgehog signaling pathway adipocyte development γ peroxisome proliferator activated receptor γ PPARγ CCAAT α CCAAT / enhancer binding protein α C / EBPα Program No 2006CB No 2009CB No No B-LJ06032 * Tel qqtang@ shmu edu cn Received July Accepted November Supported by Major State Basic Research Development Program of China 973 Program No 2006CB No 2009CB National Natural Science Foundation for Distinguished Scholars No Program for Outstanding Medical Academic Leader No B-LJ06032 * Corresponding author Tel qqtang@ shmu edu cn

2 1 Hedgehog 7 cyclopamine Hh 7 β transforming growth factor β TGFβ Smo fibroblast growth factor FGF Hedgehog Hh Wnt wingless-type MMTV integration site family members 3 Hh Hh Hh ShhIhh Dhh Gli 12 Hh 4 Hh Hh C3H10T1 /2 KS483 Hh calvaria Zehentner 2 bone morphogenesis protein 2 BMP2 Shh C3H10T1 / 1 Hh Hh 1980 Nüsslein-Volhard C3H10T1 /2 5 KS483 calvaria Shh Hh O Sonic hedgehog Shh Indian hedgehog Ihh Desert Western hedgehog Dhh 3 Hh 6 C / EBPα PPARγ Dhh Hh Ihh Shh Hh Hh Hh 12 Patched Ptc 7 Smoothened Smo Hh Gli Ptc Hh Ptcl Ptc2 Gli Hh Glil Gli2 Gli3 Gli Ci Hh Hh Ptc 18 Li Smo Smo Hh Ptc1 Ptc Hh C Hh Ptc1 mes / mes19 Hh Gli Hh Hh Ptc Smo Smo Gli2 / Gli3 Gli R Gli Ptc1 Hh Gli1 A Pparγ C / suppressor of fused SuFuHh ebpα Hh Ptc1 Hh Ptc Ptc Smo Smo Hh Gli Sufu Sufu Hh Gli A purmorphamine Ptc 9 Smo 10 Fig 1 2 Hh 2 BMP2 Shh 16 Shh Leptin 422 / ap Hh Ptc1 ap2-sufuko Hh Hh

3 8 27 Fig 1 The key components of the Hh signaling pathway Chemical matters under clinical investigation are indicated in bold 11 Five key components are required for Hh signaling the ligands the receptors the effector the regulators and the transcriptional effectors Small molecule Hh antagonists and agonist are shown in this scheme Purmorphamine is the agonist of Hh signaling pathway which acts on Smo directly to suppress this signaling pathway while cyclopamine is the antagonist of Hh signaling pathway which can interplay with Ptc and Smo to activate this signaling pathway ap2-sufuko Hh Hh 18 Suh 3T3-L1 Hh Hh Gli DNGli Hh 3T3-L1 Hh 3T3-L1 21 Shh 19 3T3-L1 3T3-L1 Pparγ GFP Shh Pparγ Hh Shh PPARγ Hh Shh Gata2 Gata Fontaine 23 Hh Gata3 DNGata3 Gata2 Gata3 Shh hmads DNGata3 hmads Shh Tong Gata2 Hh Gata3 C / EBPα C / EBPβ Hh Pparγ 3T3-F442A purmorphamine 22 Hh Gata2 /3 PPARγ hmads

4 1 Hedgehog 9 0 ~ 3 d purmorphamine 3 d 4 purmorphamine hmads Hh Hh Hh Fontaine Hh 29 Hh Hh Hh Hh 23 3 Hh References Sci Varjosalo M Taipale J J Genes Dev Hh Pospisilik 18 1 V n nen H K Mesenchymal stem cells J Ann Med Rosen E D Macdougald O A Adipocyte differentiation from the inside out J Nat Rev Mol Cell Biol Muruganandan S Roman A A Sinal C J Adipocyte differentiation of bone marrow-derived mesenchymal stem cells cross talk with the osteoblastogenic program J Cell Mol Life Hh cyclopamine J Nature Hh Genes Dev Hh Hh 1 Hh progenitor cells J Hh Hedgehog functions and mechanisms Nüsslein-Volhard C Wieschaus E Mutations affecting segment number and polarity in Drosophila J Nature Echelard Y Epstein D J St-Jacques B et al Sonic hedgehog a member of a family of putative signaling molecules is implicated in the regulation of CNS polarity J Cell Taipale J Chen J K Cooper M K et al Effects of oncogenic mutations in Smoothened and Patched can be reversed by 8 Chen J K Taipale J Cooper M K et al Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened J 9 Sinha S Chen J K Purmorphamine activates the Hedgehog pathway by targeting Smoothened J Nat Chem Biol Wu X Ding S Ding Q et al A small molecule with osteogenesis-inducing activity in multipotent mesenchymal J Am Chem Soc Tremblay M R Mcgovern K Read M A et al New developments in the discovery of small molecule Hedgehog pathway antagonists J Curr Opin Chem Biol Hh Spinella-Jaegle S Rawadi G Kawai S et al Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation

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