ISSN 1007-7626 CN 11-3870 / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2011 1 27 1 6 ~ 10 Hedgehog * 200032 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 200032 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 2 1 2010-07-07 2010-11-17 20 γ peroxisome proliferator activated receptor γ PPARγ CCAAT α CCAAT / enhancer binding protein α C / EBPα 973 973 Program No 2006CB943704 No 2009CB825604 No 30625015 No B-LJ06032 * Tel 021-54237198 E-mail qqtang@ shmu edu cn Received July 7 2010 Accepted November 17 2010 Supported by Major State Basic Research Development Program of China 973 Program No 2006CB943704 No 2009CB825604 National Natural Science Foundation for Distinguished Scholars No 30625015 Program for Outstanding Medical Academic Leader No B-LJ06032 * Corresponding author Tel 021-54237198 E-mail qqtang@ shmu edu cn
1 Hedgehog 7 cyclopamine Hh 7 β transforming growth factor β TGFβ Smo 8 2 6 9- 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 13-15 2000 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 17 18 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 Gli1 19 20 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 / ap2 12 14 Hh Ptc1 ap2-sufuko Hh Hh
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 Gata3 2008 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
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 7 469-479 24 Sci 2009 66 2 236-253 4 Varjosalo M Taipale J J Genes Dev 2008 25 Hh Pospisilik 18 1 V n nen H K Mesenchymal stem cells J Ann Med 2005 37 2 Rosen E D Macdougald O A Adipocyte differentiation from the inside out J Nat Rev Mol Cell Biol 2006 7 12 885-896 3 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 2000 406 6799 1005-1009 26 Hh Genes Dev 2002 16 21 2743-2748 Hh 1 29-30 Hh 1 Hh progenitor cells J Hh 14521 Hedgehog functions and mechanisms 22 18 2454-2472 5 Nüsslein-Volhard C Wieschaus E Mutations affecting segment number and polarity in Drosophila J Nature 1980 287 5785 795-801 6 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 1993 75 7 1417-1430 7 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 2006 2 10 Wu X Ding S Ding Q et al A small molecule with osteogenesis-inducing activity in multipotent mesenchymal J Am Chem Soc 2002 124 49 14520-11 Tremblay M R Mcgovern K Read M A et al New developments in the discovery of small molecule Hedgehog 27 28 2 pathway antagonists J Curr Opin Chem Biol 2010 428-435 3 Hh 14 3 12 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
10 27 J J Cell Sci 2001 114 Pt 11 2085-2094 13 Nakamura T Aikawa T Iwamoto-Enomoto M et al Induction of osteogenic differentiation by hedgehog proteins J Biochem Biophys Res Commun 1997 237 2 465-469 14 van der Horst G Farih-Sips H L wik CW et al Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells J Bone 2003 33 6 899-910 15 Iwamoto M Enomoto-Iwamoto M Kurisu K Actions of hedgehog proteins on skeletal cells J Crit Rev Oral Biol Med 1999 10 4 477-486 16 Zehentner B K Leser U Burtscher H BMP-2 and sonic hedgehog have contrary effects on adipocyte-like differentiation of C3H10T1 /2 cells J DNA Cell Biol 2000 19 5 275-281 17 Ashrafi K Chang F Y Watts J L et al analysis of Caenorhabditis elegans fat regulatory Nature 2003 421 6920 268-272 Genome-wide RNAi genes J 18 Pospisilik J A Schramek D Schnidar H et al Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate J Cell 2010 140 1 148-160 19 Li Z Zhang H Denhard L A et al Reduced white fat mass in adult mice bearing a truncated Patched 1 J Int J Biol Sci 2008 4 1 29-36 20 Makino S Masuya H Ishijima J et al A spontaneous mouse mutation mesenchymal dysplasia mes is caused by a deletion of the most C-terminal cytoplasmic domain of patched ptc J Dev Biol 2001 239 1 95-106 21 Suh J M Gao X Mckay J et al Hedgehog signaling plays a conserved role in inhibiting fat formation J Cell Metab 2006 3 1 25-34 22 Tong Q Tsai J Tan G et al Interaction between GATA and the C / EBP family of transcription factors is critical in GATAmediated suppression of adipocyte differentiation J Mol Cell Biol 2005 25 2 706-715 23 Fontaine C Cousin W Plaisant M et al Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells J Stem Cells 2008 26 4 1037-1046 24 Hirsch J Batchelor B Adipose tissue cellularity in human obesity J Clin Endocrinol Metab 1976 5 2 299-311 25 Virtanen K A Lidell M E Orava J et al Functional brown adipose tissue in healthy adults J N Engl J Med 2009 360 15 1518-1525 26 Duque G Bone and fat connection in aging bone J Curr Opin Rheumatol 2008 20 4 429-434 27 Buhman K K Wang L C Tang Y et al Inhibition of Hedgehog signaling protects adult mice from diet- induced weight gain J J Nutr 2004 134 11 2979-2984 28 Martin L P Lane J Pouliot L et al Increases in adipose and total body weight but not in lean body mass associated with subcutaneous administration of sonic hedgehog-ig fusion protein to mice J Drug Dev Res 2002 57 3 107-114 29 Kiselyov A S Targeting the hedgehog signaling pathway with small molecules J Anticancer Agents Med Chem 2006 6 5 445-449 2010 10 3 Nature Structural and Molecular Biology DNA Karlseder 30 75 85 9 92 DNA DNA Karlseder DNA Karlseder Science Daily Oct 4 2010