Harmine Induces Adipocyte Thermogenesis through RAC1-MEK-ERK-CHD4 Axis.
Harmine is a natural compound possessing insulin-sensitizing effect in db/db diabetic mice. However its effect on adipose tissue browning is unknown. Here we reveal that harmine antagonizes high fat diet-induced adiposity. Harmine-treated mice gained less weight on a high fat diet and displayed increased energy expenditure and adipose tissue thermogenesis. In vitro, harmine potently induced the expression of thermogenic genes in both brown and white adipocytes, which was largely abolished by inhibition of RAC1/MEK/ERK pathway. Post-transcriptional modification analysis revealed that chromodomain helicase DNA binding protein 4 (CHD4) is a potential downstream target of harmine-mediated ERK activation. CHD4 directly binds the proximal promoter region of Ucp1, which is displaced upon treatment of harmine, thereby serving as a negative modulator of Ucp1. Thus, here we reveal a new application of harmine in combating obesity via this off-target effect in adipocytes.
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Tao
T
Nie
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|HKU Shenzhen Institute of Research and Innovation, Shenzhen, China.
Xiaoyan
X
Hui
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Liufeng
L
Mao
Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Baoming
B
Nie
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Kuai
K
Li
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Wei
W
Sun
Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.
Xuefei
X
Gao
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Xiaofeng
X
Tang
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Yong
Y
Xu
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Baishan
B
Jiang
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Zhengcao
Z
Tu
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Peng
P
Li
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Ke
K
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.
Shaoping
S
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|HKU Shenzhen Institute of Research and Innovation, Shenzhen, China.
Aimin
A
Xu
Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Sheng
S
Ding
Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.
Pentao
P
Liu
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.
Adam
A
Patterson
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, U.K.|Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK; and the Centre for Endocrinology &Diabetes, Institute of Human Development, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, U.K.
Garth
G
Cooper
Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.|Joint School of Biological Sciences, Guangzhou Institute of Biomedicine and Health, Guangzhou Medical University, Guangzhou, China.
Donghai
D
Wu
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052437:Adipocytes, Brown / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects; D006247:Harmine / Q000008:administration & dosage* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D022722:Thermogenesis / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D006247:Harmine; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases; D020830:rac1 GTP-Binding Protein