2025-05-26 マックス・プランク研究所
<関連情報>
- https://www.mpg.de/24787861/0526-neur-newly-identified-group-of-nerve-cells-in-the-brain-regulates-bodyweight-153735-x
- https://www.cell.com/cell/fulltext/S0092-8674(25)00403-9
視床下部PNOC/NPYニューロンはレプチンが制御するエネルギー恒常性のメディエーターを構成する Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis
Marie H. Solheim ∙ Sima Stroganov ∙ Weiyi Chen ∙ … ∙ F. Thomas Wunderlich ∙ Lukas Steuernagel ∙ Jens C. Brüning
Cell Published:April 23, 2025
DOI:https://doi.org/10.1016/j.cell.2025.04.001
Graphical abstract
Highlights
- Loss of leptin receptors in PNOCARC neurons causes hyperphagia and obesity
- PNOC leptin receptor inactivation increases NPY expression in AgRP-/PNOC+ neurons
- Activation of NPY+/PNOC+ neurons induces feeding, similar to all PNOCARC neurons
- Overexpression of NPY in PNOCARC neurons induces hyperphagia and obesity
Summary
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.
