Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-04-23 DOI:10.1016/j.cell.2025.04.001

Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel, Jens C. Brüning

{"title":"Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis","authors":"Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel, Jens C. Brüning","doi":"10.1016/j.cell.2025.04.001","DOIUrl":null,"url":null,"abstract":"Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"17 1","pages":""},"PeriodicalIF":45.5000,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2025.04.001","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOC^ARC neurons, and overexpression of Npy in PNOC^ARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPY^ARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.

Abstract Image

查看原文本刊更多论文

下丘脑PNOC/NPY神经元是瘦素控制的能量稳态的介质

瘦素在大脑中起抑制食欲的作用，然而，瘦素的厌食作用背后的神经回路尚未完全确定。表达前pronoceptin （PNOC）的神经元介导小鼠饮食诱导的贪食和体重增加。在这里，我们发现瘦素通过PNOC神经元调节食欲和体重，而在下丘脑弓状核（ARC）表达PNOC的神经元中，瘦素受体（Lepr）的表达缺失会导致贪食和肥胖。在没有麻风基因的肥胖背景下，恢复PNOC神经元中麻风基因的表达可显著减轻体重。PNOC神经元的麻风失活增加了下丘脑PNOC神经元中不表达刺痛肽相关肽（Agrp）的神经肽Y （Npy）的表达。PNOC/NPY神经元的选择性化学激活促进摄食的程度与激活所有PNOCARC神经元的程度相同，PNOCARC神经元中NPY的过表达促进了贪食和肥胖。因此，我们将PNOC/NPYARC神经元作为瘦素作用的额外关键介质，并作为肥胖治疗的有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.