A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia

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. We especially thank the Center for Scientific Research of Anhui Medical University for providing support with the use of research equipment.

This work was supported by the National Natural Science Foundation of China (82371288, 82571376 to X. These authors contributed equally: Peng Wang, Jun Li, Xin Cheng. Department 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 Peng Wang, Jun Li, Xin Cheng, Wei Chen, Zhengyu Li, Zheng Fang, Dijia Wang, Bin Mei, Hu Liu, Zhilai Yang, Jiqian Zhang, Gaolin Qiu, Xin Qing & Xuesheng Liu School of Nursing, Anhui Medical University, Hefei, China Correspondence to Gaolin Qiu, Xin Qing or Xuesheng Liu.

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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Wang, P., Li, J., Cheng, X. et al. A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia.