Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture.
Obesity is accompanied by an increase in the size and the number of adipocytes. As adipocytes are thought to differentiate from pre-adipocytes, we postulate that non-adipogenic fibroblasts contribute to adipocyte formation under certain conditions such as obesity. We report for the first time that NIH-3T3 fibroblasts, which are generally considered to be non-adipogenic, can be converted into mature adipocytes by treatment with a defined hormone mixture comprising EGF (epidermal growth factor), HGF (hepatocyte growth factor), Dex (dexamethasone) and insulin. Furthermore, NIH-3T3 cells transplanted into obese immunodeficient NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice formed adipocytes in vivo. Interestingly, the mixture elicited conversion of NIH-3T3 cells directly into adipocytes without a preceding pre-adipocyte stage. Functional analysis revealed that each component of the mixture was necessary for the induction of adipogenesis, including Dex which inhibited the cell proliferation stimulated by EGF. Upon profiling the signalling pathways employed by EGF and HGF, we found STAT5 (signal transducer and activator of transcription 5) signalling to be activated, predominantly at the levels of both transcription and post-translational modification. Inhibition of the STAT5 pathway, either by genetic knockdown or a specific pharmacological agent, blocked adipogenesis in NIH-3T3 cells. Taken together, these data not only establish a newly recognized grouping of factors that can induce trans-differentiation of non-adipogenic fibroblasts into adipocytes, but also give us a greater understanding of obesity.
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Tao
T
Nie
†Department of Medicine, The University of Hong Kong, Hong Kong, China.
Xiaoyan
X
Hui
‡Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, U.K.
Xuefei
X
Gao
§Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, U.S.A.
Baoming
B
Nie
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Liufeng
L
Mao
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Xiaofeng
X
Tang
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Ran
R
Yuan
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Kuai
K
Li
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Peng
P
Li
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Aimin
A
Xu
‡Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, U.K.
Pengtao
P
Liu
§Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, U.S.A.
Sheng
S
Ding
║Singapore Bioimaging Consortium and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
Weiping
W
Han
¶Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, Thomas Building, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
Garth J S
GJ
Cooper
*Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China.
Donghai
D
Wu
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C553307:HGF protein, mouse; D007328:Insulin; D050799:STAT5 Transcription Factor; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D003907:Dexamethasone