Biased histamine signaling selectively gates fat preference

Nov 27, 2025Neuron

Biased histamine signals selectively control preference for fat

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Manipulating histamine H3 receptor expression in the paraventricular thalamus significantly modulates high-fat diet consumption.

High-fat-diet and high-sugar-diet responsive neurons are distinctly separated in the paraventricular thalamus.
The histamine H3 receptor is identified as a marker for specific neuronal populations in the paraventricular thalamus.
Histaminergic projections influence fat consumption based on oral dietary cues.
Histamine activation enhances neuronal excitability in the paraventricular thalamus through biased G protein signaling.
The paraventricular thalamus plays a novel role in regulating preference for fat.

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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 (HR) as a marker of PVTneurons. Manipulating HR 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 HR activation enhances PVTneuronal excitability via biased Gsignaling. These findings establish a novel role for the PVT in gating fat preference and identify the HR-Gaxis as a potential target for precise fat-consumption control. 3 3 3 12/13 3 12/13HFD HFD

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Biased histamine signaling selectively gates fat preference

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