Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Department of Clinical Biochemistry and the Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education, Chongqing Medical University, Chongqing, China.
Theranostics. 2024 Oct 7;14(17):6605-6624. doi: 10.7150/thno.96480. eCollection 2024.
The multifaceted functions of p62 (SQSTM1) are increasingly recognized, but its role in hypothalamic metabolism-associated neurons for energy balance has yet to be elucidated.
Single-nucleus RNA sequencing (snRNA-Seq) was performed on hypothalamic tissues from db/db and db/m mice to explore p62 expression. Overexpression and knockout of p62 in hypothalamic POMC neurons were performed AAV-mediated gene delivery and Cre-loxP systems. Metabolic outcomes were assessed under normal chow (NCD) and high-fat diet (HFD) conditions. The co-immunoprecipitation and luciferase reporter assays were used to investigate the interaction between p62 and STAT3.
The snRNA-Seq analysis found that p62 was ubiquitously expressed in hypothalamic neurons, with significantly higher levels in POMC neurons of db/db mice compared to db/m controls. Under NCD or HFD conditions, the absence of p62 in POMC neurons led to increased body weight, decreased energy expenditure and leptin sensitivity, while its overexpression in POMC neurons produced the opposite phenotype. Mechanistically, p62 interacts with STAT3, facilitating its phosphorylation to initiate POMC transcription and amplify leptin sensitivity.
This study demonstrated the capacity of p62 to monogenically regulate the obesity phenotype and emphasized its dual role in managing energy homeostasis through direct modulation of STAT3/POMC signaling and amplification of leptin sensitivity.
p62（SQSTM1）的多方面功能日益得到认可，但它在与下丘脑代谢相关的神经元中对能量平衡的作用尚未阐明。
对 db/db 和 db/m 小鼠的下丘脑组织进行单细胞核 RNA 测序（snRNA-Seq），以探索 p62 的表达情况。通过 AAV 介导的基因传递和 Cre-loxP 系统在下丘脑 POMC 神经元中过表达和敲除 p62。在正常饮食（NCD）和高脂肪饮食（HFD）条件下评估代谢结果。使用免疫共沉淀和荧光素酶报告基因测定来研究 p62 和 STAT3 之间的相互作用。
snRNA-Seq 分析发现，p62 在下丘脑神经元中广泛表达，db/db 小鼠的 POMC 神经元中表达水平明显高于 db/m 对照组。在 NCD 或 HFD 条件下，POMC 神经元中 p62 的缺失导致体重增加、能量消耗减少和瘦素敏感性降低，而 POMC 神经元中 p62 的过表达则产生相反的表型。机制上，p62 与 STAT3 相互作用，促进其磷酸化，从而启动 POMC 转录并放大瘦素敏感性。
这项研究表明 p62 能够单基因调节肥胖表型，并强调其通过直接调节 STAT3/POMC 信号和放大瘦素敏感性来调节能量平衡的双重作用。
