Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice
Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice
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DOI：
10.1101/2021.06.26.450020
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发表时间：
2021-06
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通讯作者：
Jo E. Lewis;Orla R. M. Woodward;Danaé Nuzzaci;Christopher A. Smith;Alice E. Adriaenssens;Lawrence J. Billing;Cheryl A. Brighton;Benjamin U Phillips;J. Tadross;S. Kinston;E. Ciabatti;B. Göttgens;Marco Tripodi;D. Hornigold;David Baker;F. Gribble;F. Reimann
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作者：
Jo E. Lewis;Orla R. M. Woodward;Danaé Nuzzaci;Christopher A. Smith;Alice E. Adriaenssens;Lawrence J. Billing;Cheryl A. Brighton;Benjamin U Phillips;J. Tadross;S. Kinston;E. Ciabatti;B. Göttgens;Marco Tripodi;D. Hornigold;David Baker;F. Gribble;F. Reimann
松弛素/胰岛素样肽家族受体-4（RXFP 4），胰岛素样肽5（INSL 5）的同源受体，已经涉及进食行为，因为RxFP 4敲除小鼠显示出更短的进食持续时间和减少的高脂肪饮食（HFD）摄入。在这里，我们产生转基因Rxfp 4-Cre小鼠，以探索Rxfp 4的表达和生理。使用该模型，我们确定了Rxfp 4在中枢神经系统中的表达，包括在下丘脑腹内侧（VMH）。INSL 5的VMH内输注增加了随意喂养的野生型小鼠的HFD和高度可口的液体膳食摄入（HPM）。VMH Rxfp 4表达细胞（RXFP 4VMH）的单细胞RNA测序确定了一组Rxfp 4标记的神经元，这些神经元表达Esr 1，Tac 1和Oxtr，以及已知的食欲调节神经肽受体（Mc 4 r，Cckar和Nmur 2）。病毒示踪显示RXFP 4VMH神经投射到终纹床核、下丘脑室旁核、丘脑脑室旁核和杏仁核中央核。利用专门由设计药物激活的设计受体（DREADD），我们发现Rxfp 4表达细胞的全身化学发生抑制（Di），模拟天然INSL 5-RXFP 4信号传导，增加HFD和HPM的摄入，而在全身水平或特别是VMH内的激活（Dq）减少HFD和HPM摄入并改变食物偏好。扩增VMH Rxfp 4表达细胞重现了Rxfp 4敲除小鼠的较低HFD摄入表型，导致体重减轻。这些研究结果确定了一个离散的RXFP 4表达神经元群体作为食物摄入和偏好的关键调节因子，并揭示了下丘脑RXFP 4信号传导作为摄食行为操纵的靶点。
Relaxin/insulin-like-family peptide receptor-4 (RXFP4), the cognate receptor for insulin-like peptide 5 (INSL5), has been implicated in feeding behaviour as Rxfp4 knockout mice display shorter meal durations and reduced high fat diet (HFD) intake. Here, we generated transgenic Rxfp4-Cre mice to explore Rxfp4 expression and physiology. Using this model, we identified Rxfp4 expression in the central nervous system, including in the ventromedial hypothalamus (VMH). Intra-VMH infusion of INSL5 increased HFD and highly palatable liquid meal intake (HPM) of ad libitum fed wildtype mice. Single-cell RNA-sequencing of VMH Rxfp4-expressing cells (RXFP4VMH) defined a cluster of Rxfp4-labelled neurons expressing Esr1, Tac1 and Oxtr, alongside known appetite-modulating neuropeptide receptors (Mc4r, Cckar and Nmur2). Viral tracing demonstrated RXFP4VMH neural projections to the bed nucleus of the stria terminalis, paraventricular hypothalamus, paraventricular thalamus and central nucleus of the amygdala. Utilising designer receptors exclusively activated by designer drugs (DREADDs), we found that whole body chemogenetic inhibition (Di) of Rxfp4-expressing cells, mimicking native INSL5-RXFP4 signalling, increased intake of HFD and HPM, whilst activation (Dq), either at whole body level or specifically within the VMH, reduced HFD and HPM intake and altered food preference. Ablating VMH Rxfp4-expressing cells recapitulated the lower HFD intake phenotype of Rxfp4 knockout mice, resulting in reduced body weight. These findings identify a discrete Rxfp4-expressing neuronal population as a key regulator of food intake and preference and reveal hypothalamic RXFP4 signalling as a target for feeding behaviour manipulation.