2. Academic Validation
  3. Biased histamine signaling selectively gates fat preference

Biased histamine signaling selectively gates fat preference

  • Neuron. 2025 Nov 26:S0896-6273(25)00842-6. doi: 10.1016/j.neuron.2025.10.035.
Yanrong Zheng 1,  Jie Liao 2,  Zhuowen Fang 3,  Xinyan Tang 4,  Zhuchen Zhou 1,  Xinyue Zhao 1,  Menghan Li 1,  Mengting Liu 1,  Shujun Xu 3,  Jiahui Chen 3,  Lingyu Xu 1,  Yi Wang 1,  Yan Zhang 4,  Weiwei Hu 4,  Zhong Chen 5
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; State Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, Zhejiang, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 4 School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 5 Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China. Electronic address: [email protected].
PMID: 41308645 DOI: 10.1016/j.neuron.2025.10.035
Abstract

Fat poses a serious challenge to healthy dietary management due to its unique palatability and high energy density. Previous studies indicate that sugar and fat are independently perceived in the periphery, yet identifying molecular targets for selectively regulating fat preference remains a challenge. Here, using neuronal activity-dependent labeling, we identified a striking separation between high-fat-diet (HFD)- and high-sugar-diet (HSD)-responsive neuronal populations in the paraventricular thalamus (PVT). Translating ribosome affinity purification Sequencing and in situ hybridization further revealed the histamine H3 receptor (H3R) as a marker of PVTHFD neurons. Manipulating H3R expression or histaminergic terminals in the PVT specifically modulated HFD consumption. These histaminergic projections regulate fat consumption in response to oral dietary cues. Electrophysiological analyses demonstrated that histamine-mediated H3R activation enhances PVTHFD neuronal excitability via biased G12/13 signaling. These findings establish a novel role for the PVT in gating fat preference and identify the H3R-G12/13 axis as a potential target for precise fat-consumption control.

Keywords

biased GPCR signaling; fat preference; histamine H3 receptor; paraventricular thalamus; sugar preference.

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