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Glutamine production by Glul promotes thermogenic adipocyte differentiation through Prdm9-mediated H3K4me3 and transcriptional reprogramming

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posted on 2023-08-14, 20:28 authored by Xiaowen Pan, Lingxia Ye, Xiaozhen Guo, Weihua Wang, Ziyin Zhang, Qintao Wang, Jingjing Huang, Jingya Xu, Yanhan Cai, Xinxin Shou, Yuting Wang, Yu Feng, Cen Xie, Pengfei Shan, Zhuo-Xian Meng

Abstract
Thermogenic adipocytes have been extensively investigated due to 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 cell-autonomously stimulates BAC differentiation and function, BAT tissue remodeling, and improves 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. Further, 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.


Article Highlight:

• Glutamine is a pivotal player in multiple biological processes and disease progression. However, its role in thermogenic adipocyte differentiation and function remains unclear.

• Through genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels, we investigated the role and mechanism of Glul/glutamine pathway in adipocyte thermogenesis and systemic homeostasis.

• We revealed that Glul-mediated glutamine production is critical for BAC differentiation, and uncovered an unexpected role of C/EBPb-Prdm9-mediated histone methylation and transcriptional reprogramming in this process.

• This work highlights the therapeutic and translational potential of targeting the Glul/glutamine/Prdm9 pathway to treat obesity and associated metabolic diseases.

Funding

"National Tutor System" Training Program for Youth Talents of Suzhou Health Care System x Qngg2021007

Construction Fund of Medical Key Disciplines of Hangzhou

Fundamental Research Funds for the Central Universities

Innovative Institute of Basic Medical Sciences of Zhejiang University

National Key Research and Development Programme of China x 2018YFA0800403

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 81670740 81670744 81870564 82070838

National Natural Science Fund for Excellent Young Scholars of China x 81722012

Science Technology Department of Zhejiang Province of China x 2017C33037

Training Program of the Major Research Plan of the National Natural Science Foundation of China x 91857110

Zhejiang Provincial Natural Science Foundation of China x LZ21H070001

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