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.
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Research Article|
April 17 2015
Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture
Tao Nie;
Tao 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Xiaoyan Hui;
Xiaoyan Hui
†Department of Medicine, The University of Hong Kong, Hong Kong, China
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Xuefei Gao;
Xuefei Gao
‡Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, U.K.
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Baoming Nie;
Baoming Nie
§Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, U.S.A.
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Liufeng Mao;
Liufeng 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Xiaofeng Tang;
Xiaofeng 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Ran Yuan;
Ran 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Kuai Li;
Kuai 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Peng Li;
Peng 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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Aimin Xu;
Aimin Xu
*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
†Department of Medicine, The University of Hong Kong, Hong Kong, China
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Pengtao Liu;
Pengtao Liu
‡Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, U.K.
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Sheng Ding;
Sheng Ding
§Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, U.S.A.
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Weiping Han;
Weiping Han
║Singapore Bioimaging Consortium and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Garth J. S. Cooper;
Garth J. S. Cooper
¶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
**Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
††Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, U.K.
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
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Donghai Wu
Donghai Wu
1
*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
‡†Centre for Endocrinology and Diabetes, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, U.K.
1To whom correspondence should be addressed (email wu_donghai@gibh.ac.cn).
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Biochem J (2015) 467 (3): 487–494.
Article history
Received:
June 11 2014
Revision Received:
January 22 2015
Accepted:
March 02 2015
Accepted Manuscript online:
March 02 2015
Citation
Tao Nie, Xiaoyan Hui, Xuefei Gao, Baoming Nie, Liufeng Mao, Xiaofeng Tang, Ran Yuan, Kuai Li, Peng Li, Aimin Xu, Pengtao Liu, Sheng Ding, Weiping Han, Garth J. S. Cooper, Donghai Wu; Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture. Biochem J 1 May 2015; 467 (3): 487–494. doi: https://doi.org/10.1042/BJ20140727
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