SAHA induces white fat browning and rectifies metabolic dysfunctions via activation of ZFPs

in Journal of Endocrinology
Authors:
Jinyu Ma Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China

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Yuejun Wang Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China

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Jie Ding Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China

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Shouping Zhang Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China

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Yinuo Yang Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China

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Cheng Sun Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University,Nantong, China
Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Institute of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China

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Correspondence should be addressed to C Sun: suncheng1975@ntu.edu.cn
DOI:
https://doi.org/10.1530/JOE-20-0472
Volume/Issue:
Volume 249: Issue 3
Article Type:
Research Article
Page Range:
177–193
Online Publication Date:
06 May 2021
Copyright:
© 2021 Society for Endocrinology 2021
Restricted access
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Several histone deacetylase (HDAC) inhibitors have been shown to play beneficial roles in treating obesity and its related metabolic syndromes. However, the underlying mechanisms are still not understood well. In this study, we examined the potential roles of SAHA, a potent inhibitor of HDACs, on energy expenditure and explored the molecular mechanism involved. Our data showed that SAHA induces less lipid accumulation and smaller lipid droplets in cultured adipocytes. In vivo studies showing SAHA reduces body weight gain and increases core temperature in lean and obese mice. Furthermore, SAHA accelerates blood glucose disposal, improves insulin sensitivity and attenuates fatty liver in obese animals. Transcriptome sequencing found that a group of zinc finger proteins (Zfps) was up-regulated by SAHA. Functional studies showed that the knockdown of Zfp691 or Zfp719 largely abolishes SAHA-induced Ucp1 expression in adipocytes. ChIP assay showed that SAHA stimulates histone H3 acetylation at Zfp719 promoter. Luciferase reporter analysis revealed that Zfp719 activates Ucp1 promoter. As a consequence, forced expression of Zfp719 increases Ucp1 expression and promotes lipid catabolism in adipocytes. Taken together, our data indicate that by stimulating axis of ZFPs-UCP1, SAHA induces white fat browning and energy consumption, which makes it a potential drug for treating obesity and related metabolic dysfunctions.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
17
Article Type:
Research Article
Received Date:
23 Mar 2021
Accepted Date:
15 Apr 2021
Print Publication Date:
01 Jun 2021
Online Publication Date:
06 May 2021
Keywords:
SAHA; HDAC inhibitor; obesity; white fat browning; zinc finger proteins

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