Negative feedback regulation of alcohol ingestion through the FGF21-PVH oxytocin-VTA dopamine system
Alcohol has a notable negative impact on global health. Understanding its physiological regulation is crucial to addressing alcohol use. Here, we show that FGF21-oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVH<sup>OXT</sup>)-dopamine neurons in the ventral tegmental area (VTA<sup>DA</sup>) negatively regulate the drive to drink alcohol. Alcohol induces FGF21 signaling, which activates PVH<sup>OXT</sup> and induces oxytocin release in the VTA. The VTA<sup>DA</sup> neurons are activated hours after alcohol ingestion, which reduces the drive to drink alcohol, extends the interdrink interval, and thereby reduces alcohol consumption. The system is downregulated in a mouse model of alcohol dependence, and activating the system with FGF21-inducing sugars reduces alcohol ingestion and prevents binge drinking and alcohol dependence. Therefore, FGF21-inducing nutraceuticals can substitute for alcohol by supplementing the FGF21-PVH<sup>OXT</sup>-VTA<sup>DA</sup> negative feedback signal to attenuate alcohol-related behaviors in mice.
Authors
- Satoshi Tsuzuki (ORCID: https://orcid.org/0000-0003-4385-0075)
- S Matsui
- Kazuhiro Umemoto
- Takatoshi Hikida (ORCID: https://orcid.org/0000-0002-8653-311X)
- Yasuo Oguri (ORCID: https://orcid.org/0000-0002-7435-6961)
- T. Sasaki
- Yuma Takahashi
- Takaaki Ozawa (ORCID: https://orcid.org/0000-0003-3633-7062)
- Hiroki Iwama
- Lan Geng
- Sachiho Kanayama
- Yulong Li
- Shuhei Morioka
Institutions
- McGovern Institute for Brain Research (US)
- Peking University (CN)
- Kyoto University (JP)
- Ube Frontier University (JP)
- Center for Life Sciences (CN)
- The University of Osaka (JP)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-01-14
- DOI
- https://doi.org/10.1073/pnas.2525172122
- Primary Topic
- Neuroendocrine regulation and behavior
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Suzuken Memorial Foundation
- Kowa Company
- Urakami Foundation for Food and Food Culture Promotion
- Kato Memorial Bioscience Foundation
- Kowa Life Science Foundation
- Lotte Foundation
- TOBE MAKI Scholarship Foundation
- Japan Society for the Promotion of Science
- Institute for Protein Research, Osaka University