A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia.
6 affiliations
- 1Department of Anaesthesiology, the First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anaesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
- 2School of Nursing, Anhui Medical University, Hefei, China.
- 3Department of Anaesthesiology, the First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anaesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China. [email protected].
- 4Department of Anaesthesiology, the First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anaesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China. [email protected].
- 5Department of Anaesthesiology, the First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anaesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China. [email protected].
- 6School of Nursing, Anhui Medical University, Hefei, China. [email protected].
Abstract
Obesity and anxiety disorders are frequently comorbid, yet the neural circuit mechanisms linking metabolic and affective states remain incompletely understood. Here, in male mice exposed to long-term high-fat diet, we identify a hypothalamic circuit comprising arcuate nucleus agouti-related protein neurons and paraventricular nucleus corticotropin-releasing hormone neurons that regulates anxiety-like behavior under metabolic stress, with downstream recruitment of lateral hypothalamic area glutamatergic neurons to modulate feeding in a state-dependent manner. In vivo fiber photometry and ex vivo electrophysiology show that high-fat diet enhances activity and feeding-locked recruitment of this circuit, associated with increased anxiety-like behavior and feeding. Circuit-specific inhibition attenuates both phenotypes, whereas corticotropin-releasing hormone receptor 2 signaling in the lateral hypothalamic area selectively mediates high-fat diet-associated hyperphagia without affecting anxiety-like behavior. In this work, we show a disease-state-dependent hypothalamic circuit differentially recruited under chronic high-fat diet to coordinate anxiety-related behavior and feeding output, providing a framework for metabolic-affective interactions.
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BibTeX
@article{wang2026hypothalamic,
title = {{A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia.}},
author = {Peng Wang and Jun Li and Xin Cheng and Wei Chen and Zhengyu Li and Zheng Fang and Dijia Wang and Bin Mei and Hu Liu and Shaohua Hu and Zhilai Yang and Jiqian Zhang and Gaolin Qiu and Xin Qing and Xuesheng Liu},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77749-w},
url = {https://europepmc.org/article/MED/42893998},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia.
AU - Peng Wang
AU - Jun Li
AU - Xin Cheng
AU - Wei Chen
AU - Zhengyu Li
AU - Zheng Fang
AU - Dijia Wang
AU - Bin Mei
AU - Hu Liu
AU - Shaohua Hu
AU - Zhilai Yang
AU - Jiqian Zhang
AU - Gaolin Qiu
AU - Xin Qing
AU - Xuesheng Liu
PY - 2026
DA - 2026/09/16
JO - Nature communications
DO - 10.1038/s41467-026-77749-w
UR - https://europepmc.org/article/MED/42893998
AB - Obesity and anxiety disorders are frequently comorbid, yet the neural circuit mechanisms linking metabolic and affective states remain incompletely understood. Here, in male mice exposed to long-term high-fat diet, we identify a hypothalamic circuit comprising arcuate nucleus agouti-related protein neurons and paraventricular nucleus corticotropin-releasing hormone neurons that regulates anxiety-like behavior under metabolic stress, with downstream recruitment of lateral hypothalamic area glutamatergic neurons to modulate feeding in a state-dependent manner. In vivo fiber photometry and ex vivo electrophysiology show that high-fat diet enhances activity and feeding-locked recruitment of this circuit, associated with increased anxiety-like behavior and feeding. Circuit-specific inhibition attenuates both phenotypes, whereas corticotropin-releasing hormone receptor 2 signaling in the lateral hypothalamic area selectively mediates high-fat diet-associated hyperphagia without affecting anxiety-like behavior. In this work, we show a disease-state-dependent hypothalamic circuit differentially recruited under chronic high-fat diet to coordinate anxiety-related behavior and feeding output, providing a framework for metabolic-affective interactions.
SN - 2041-1723
ER -