Han Hongdong, Li Qinge, Wang Cong, Liang Zerong, Zhang Lianying, Zhang Siliang, Tian Mingyuan, Li Shengbing, Liu Dongfang, Yang Gangyi, Yang Mengliu, Li Ling
Department of Clinical Biochemistry and The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education, Chongqing Medical University, Chongqing, China.
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
J Adv Res. 2025 Jul 21. doi: 10.1016/j.jare.2025.07.028.
B-cell leukemia/lymphoma 6 (BCL6) has been implicated in regulating energy metabolism in peripheral tissues; however, its role in the hypothalamic regulation of energy homeostasis remains poorly defined.
This study aimed to investigate the role of hypothalamic BCL6 signaling in the regulation of energy homeostasis and metabolism.
We first examined the expression patterns of BCL6 in the hypothalamus via bulk RNA sequencing (bulk RNA-Seq) and single-nucleus RNA sequencing (snRNA-Seq), followed by validation of the sequencing results. To assess the functional role of BCL6 in hypothalamic energy regulation, we performed gain- and loss-of-function experiments in POMC neurons from diet-induced obese mice. Metabolic phenotyping, histological analysis, and gene and protein expression assays were conducted to evaluate the impact of BCL6 on whole-body energy metabolism. Additionally, we reanalyzed the BCL6 ChIP-seq data and performed luciferase assays, ChIP-qPCR, Co-IP, and site-directed mutagenesis to elucidate the molecular mechanism underlying the interaction between BCL6 and Stat3.
We found that Bcl6 was expressed in the hypothalamus of mice and upregulated in both diet-induced obesity (DIO) and ob/ob mice. The overexpression of Bcl6 in POMC neurons promoted food intake and weight gain and reduced energy expenditure under high-fat diet (HFD) conditions. These effects were associated with decreased POMC expression and STAT3 phosphorylation. Conversely, Bcl6 deletion in POMC neurons produced opposite metabolic phenotypes. The deletion of Stat3 in POMC neurons abolished the metabolic benefits of hypothalamic Bcl6 knockdown. Mechanistically, we showed that BCL6 directly binds to the Stat3 promotor, inhibiting its transcription through SIRT1-mediated H4K16ac and H1.4K26ac deacetylation.
Our findings demonstrate that BCL6 in hypothalamic POMC neurons acts as a key regulator of energy metabolism.
B细胞白血病/淋巴瘤6（BCL6）已被证实参与调节外周组织的能量代谢；然而，其在下丘脑能量稳态调节中的作用仍不清楚。
本研究旨在探讨下丘脑BCL6信号通路在能量稳态和代谢调节中的作用。
我们首先通过批量RNA测序（bulk RNA-Seq）和单核RNA测序（snRNA-Seq）检测下丘脑BCL6的表达模式，随后对测序结果进行验证。为评估BCL6在下丘脑能量调节中的功能作用，我们在饮食诱导肥胖小鼠的促黑素细胞激素（POMC）神经元中进行了功能获得和功能丧失实验。进行代谢表型分析、组织学分析以及基因和蛋白质表达检测，以评估BCL6对全身能量代谢的影响。此外，我们重新分析了BCL6染色质免疫沉淀测序（ChIP-seq）数据，并进行了荧光素酶检测、ChIP定量聚合酶链反应（ChIP-qPCR）、免疫共沉淀（Co-IP）和定点诱变，以阐明BCL6与信号转导和转录激活因子3（Stat3）相互作用的分子机制。
我们发现Bcl6在小鼠下丘脑中表达，并在饮食诱导肥胖（DIO）小鼠和ob/ob小鼠中上调。在高脂饮食（HFD）条件下，POMC神经元中Bcl6的过表达促进了食物摄入和体重增加，并降低了能量消耗。这些效应与POMC表达降低和STAT3磷酸化减少有关。相反，POMC神经元中Bcl6的缺失产生了相反的代谢表型。POMC神经元中Stat3的缺失消除了下丘脑Bcl6基因敲低的代谢益处。从机制上讲，我们表明BCL6直接结合Stat3启动子，通过沉默信息调节因子1（SIRT1）介导的组蛋白H4第16位赖氨酸乙酰化（H4K16ac）和组蛋白H1.4第26位赖氨酸乙酰化（H1.4K26ac）去乙酰化来抑制其转录。
我们的研究结果表明，下丘脑POMC神经元中的BCL6是能量代谢的关键调节因子。
