Leukemia Inhibitory Factor and Its Receptor Promote Adipocyte Differentiation via the Mitogen-activated Protein Kinase Cascade*
- Jerome Aubert‡,
- Sophie Dessolin‡,
- Nathalie Belmonte‡,
- Meng Li§,
- Fergus R. McKenzie‡,
- Laurence Staccini‡,
- Phi Villageois‡,
- Brigitte Barhanin‡,
- Ann Vernallis¶,
- Austin G. Smith§,
- Gérard Ailhaud‡ and
- Christian Dani‡‖
- From the ‡Centre de Biochimie (IFR349 and UMR6543 CNRS) Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose, 06108 Nice, France, the §Centre for Genome Research, University of Edinburgh, Edinburgh, EHG3JQ Scotland, United Kingdom, and the ¶School of Life and Health Sciences, Aston University, Birmingham B47HET, United Kingdom
Abstract
Extracellular factors and intracellular signaling pathways involved in early events of adipocyte differentiation are poorly defined. It is shown herein that expression of leukemia inhibitory factor (LIF) and LIF receptor is developmentally regulated during adipocyte differentiation. Preadipocytes secrete bioactive LIF, and an antagonist of LIF receptor inhibits adipogenesis. Genetically modified embryonic stem (ES) cells combined with culture conditions to commit stem cells into the adipocyte lineage were used to examine the requirement of LIF receptor during in vitro development of adipose cells. The capacity of embryoid bodies derived fromlifr −/− ES cells to undergo adipocyte differentiation is dramatically reduced. LIF addition stimulates adipocyte differentiation of Ob1771 and 3T3-F442A preadipocytes and that of peroxisome proliferator-activated receptor γ2 ligand-treated mouse embryonic fibroblasts. Expression of the early adipogenic transcription factors C/EBPβ and C/EBPδ is rapidly stimulated following exposure of preadipose cells to LIF. The selective inhibitors of mitogen-activated protein kinase kinase, i.e. PD98059 and U0126, inhibit LIF-induced C/EBP gene expression and prevent adipocyte differentiation induced by LIF. These results are in favor of a model that implicates stimulation of LIF receptor in the commitment of preadipocytes to undergo terminal differentiation by controlling the early expression of C/EBPβ and C/EBPδ genes via the mitogen-activated protein kinase cascade.
Footnotes
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↵* This work was supported by the Centre National de la Recherche Scientifique Grant UMR6543, the Institut National de la Santé et de la Recherche Médicale, the Royal Society (European Science Exchange Program (to A. S. and C. D.)), and the Association pour la Recherche Contre le Cancer Grants 5065 and 9982 (to C. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Centre de Biochimie (UMR6543 CNRS) Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose, 06108 Nice Cedex 2, France. Tel.: 33-4-92-07-64-36; Fax: 33-4-92-07-64-04; E-mail: dani@unice.fr.
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↵2 M. Li and A. G. Smith, submitted for publication.
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↵3 J. Aubert and C. Dani, unpublished data.
- Abbreviations:
- C/EBP
-
CAAT/enhancer binding proteins
- ES cells
-
embryonic stem cells
- LIF
-
leukemia inhibitory factor
- MAPK
-
mitogen-activated protein kinase
- PPAR
-
peroxisome proliferator-activated receptor
- FCS
-
fetal calf serum
- MEF
-
mouse embryonic fibroblasts
- IL-6
-
interleukin-6
- sIL-6R
-
soluble IL-6 receptor
- GPDH
-
glycerol-phosphate dehydrogenase
- CNTF
-
ciliary neurotrophic factor
- gp
-
glycoprotein
- STAT
-
signal transducers and activators of transcription
- CT
-
cardiotrophin
-
- Received April 16, 1999.
- Revision received May 24, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
