Chandelier
Senior Member (Voting Rights)
Biased histamine signaling selectively gates fat preference
• Histamine H3 receptors (H3Rs) are a defining molecular marker of PVTHFD neurons
• H3Rs in the PVT selectively regulate HFD consumption via G12/13 signaling
• TMNHA → PVTHFD circuit regulates fat intake in response to orosensory cues
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 PVTHFDneurons.
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 G12/13signaling.
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.
Web | DOI | Neuron
Zheng, Yanrong; Liao, Jie; Fang, Zhuowen; Tang, Xinyan; Zhou, Zhuchen; Zhao, Xinyue; Li, Menghan; Liu, Mengting; Xu, Shujun; Chen, Jiahui; Xu, Lingyu; Wang, Yi; Zhang, Yan; Hu, Weiwei; Chen, Zhong
Highlights
• Two distinct sub-clusters of PVT neurons mediate HFD and HSD intake, respectively• Histamine H3 receptors (H3Rs) are a defining molecular marker of PVTHFD neurons
• H3Rs in the PVT selectively regulate HFD consumption via G12/13 signaling
• TMNHA → PVTHFD circuit regulates fat intake in response to orosensory cues
Summary
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 PVTHFDneurons.
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 G12/13signaling.
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.
Graphical abstract
Web | DOI | Neuron