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Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming

文献类型：期刊论文

作者Pan, Xiaowen1,2,3; Ye, Lingxia4; Guo, Xiaozhen; Wang, Weihua1,2,3; Zhang, Ziyin1,2,3; Wang, Qintao1,2,3; Huang, Jingjing4; Xu, Jingya1,2,3; Cai, Yanhan4; Shou, Xinxin1,2
刊名DIABETES
出版日期2023-11-01
卷号72期号:11页码:24
ISSN号0012-1797
DOI10.2337/db23-0162
通讯作者Shan, Pengfei(pengfeishan@zju.edu.cn) ; Meng, Zhuo-Xian(zxmeng@zju.edu.cn)
英文摘要Thermogenic adipocytes have been extensively investigated because of their energy-dissipating property and therapeutic potential for obesity and diabetes. Besides serving as fuel sources, accumulating evidence suggests that intermediate metabolites play critical roles in multiple biological processes. However, their role in adipocyte differentiation and thermogenesis remains unexplored. Here, we report that human and mouse obesity is associated with marked downregulation of glutamine synthetase (Glul) expression and activity in thermogenic adipose tissues. Glul is robustly upregulated during brown adipocyte (BAC) differentiation and in brown adipose tissue (BAT) upon cold exposure and Cl316,243 stimulation. Further genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels reveal that glutamine cells autonomously stimulate BAC differentiation and function and BAT remodeling and improve systemic energy homeostasis in mice. Mechanistically, glutamine promotes transcriptional induction of adipogenic and thermogenic gene programs through histone modification-mediated chromatin remodeling. Among all the glutamine-regulated writer and eraser genes responsible for histone methylation and acetylation, only Prdm9, a histone lysine methyltransferase, is robustly induced during BAC differentiation. Importantly, Prdm9 inactivation by shRNA knockdown or a selective inhibitor attenuates glutamine-triggered adipogenic and thermogenic induction. Furthermore, Prdm9 gene transcription is regulated by glutamine through the recruitment of C/EBPb to its enhancer region. This work reveals glutamine as a novel activator of thermogenic adipocyte differentiation and uncovers an unexpected role of C/EBPb-Prdm9-mediated H3K4me3 and transcriptional reprogramming in adipocyte differentiation and thermogenesis.
WOS关键词SATURATED FATTY-ACIDS ; BROWN ADIPOSE-TISSUE ; ORAL GLUCOSE-TOLERANCE ; CORONARY-HEART-DISEASE ; INSULIN SENSITIVITY ; AMINO-ACIDS ; BEIGE FAT ; CELL ; METABOLISM ; OBESITY
资助项目National Key Research and Development Program of China[2018YFA0800403] ; Training Program of the Major Research Plan of the National Natural Science Foundation of China[91857110] ; National Natural Science Fund for Excellent Young Scholars of China[81722012] ; National Natural Science Foundation of China[81870564] ; National Natural Science Foundation of China[81670744] ; National Natural Science Foundation of China[82070838] ; National Natural Science Foundation of China[81670740] ; Zhejiang Provincial Natural Science Foundation of China[LZ21H070001] ; Zhejiang Provincial Natural Science Foundation of China[LHDMD22H02001] ; Innovative Institute of Basic Medical Sciences of Zhejiang University ; Fundamental Research Funds for the Central Universities ; Construction Fund of Medical Key Disciplines of Hangzhou ; Science Technology Department of Zhejiang Province of China[2017C33037] ; National Tutor System Training Program for Youth Talents of Suzhou Health Care System[Qngg2021007] ; K.C. Wong Education Foundation
WOS研究方向Endocrinology & Metabolism
语种英语
出版者AMER DIABETES ASSOC
WOS记录号WOS:001126701500007
源URL[http://119.78.100.183/handle/2S10ELR8/309545]  
专题中国科学院上海药物研究所
通讯作者Shan, Pengfei; Meng, Zhuo-Xian
作者单位1.Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Hangzhou, Zhejiang, Peoples R China
2.Zhejiang Univ, Sch Med, Dept Cardiol, Affiliated Hosp 2, Hangzhou, Zhejiang, Peoples R China
3.Zhejiang Univ, Sch Med, Key Lab Dis Prote Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China
4.Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Endocrinol & Metab, Hangzhou, Zhejiang, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
6.Soochow Univ, Affiliated Hosp 2, Dept Endocrinol, Suzhou, Peoples R China
7.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med, Dept Geriatr, Hangzhou, Zhejiang, Peoples R China
8.Zhejiang Univ, Sch Publ Hlth, Chron Dis Res Inst, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Pan, Xiaowen,Ye, Lingxia,Guo, Xiaozhen,et al. Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming[J]. DIABETES,2023,72(11):24.
APA Pan, Xiaowen.,Ye, Lingxia.,Guo, Xiaozhen.,Wang, Weihua.,Zhang, Ziyin.,...&Meng, Zhuo-Xian.(2023).Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming.DIABETES,72(11),24.
MLA Pan, Xiaowen,et al."Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming".DIABETES 72.11(2023):24.

入库方式： OAI收割

来源：上海药物研究所

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