表达 GFRAL 的神经元通过厌恶途径抑制摄食。
GFRAL-expressing neurons suppress food intake via aversive pathways.
机构信息
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Department of Surgery, University of Michigan, Ann Arbor, MI 48109.
出版信息
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2021357118.
The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated and conditional mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRP) neurons. Silencing CGRP neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.
TGFβ 细胞因子家族成员 GDF-15 可减少食物摄入和体重，代表了肥胖治疗的一种潜在方法。由于其受体 GDNF 家族受体 α 样（GFRAL）的脑干限制表达模式，为理解孤束核神经元在食物摄入中的作用机制提供了一个令人兴奋的机会；我们生成了 和条件性 小鼠以可视化和操纵 GFRAL 神经元。我们发现感染或病理生理状态（而不是进餐）刺激 GFRAL 神经元。对 GFRAL 神经元的 TRAP-Seq 分析显示它们表达了广泛的神经递质和神经肽。人工激活 -表达神经元抑制摄食，减少胃排空，并促进条件性味觉厌恶（CTA）。GFRAL 神经元强烈支配臂旁核（PBN），在那里它们靶向 CGRP 表达（CGRP）神经元。沉默 CGRP 神经元消除了 GDF-15 的厌恶和厌食作用。这些发现表明，GFRAL 神经元将非进餐相关的病理生理信号联系起来，以抑制营养物质的摄取和吸收。
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