美国莫奈尔化学感官中心Amber L. Alhadeff团队近期取得重要工作进展，他们研究发现了相互独立发挥功能的后脑GLP1R饱腹感和厌恶感回路。相关研究成果2024年7月10日在线发表于《自然》杂志上。

据介绍，最成功的肥胖治疗药物，胰高血糖素样肽-1受体（GLP1R）激动剂，会引起恶心和呕吐等不良反应，这些反应可能有助于其疗效。

研究人员探讨了将饱腹感与厌恶联系起来的大脑回路，发现介导这些效应的神经回路在功能上是可分离的。对药物可及GLP1R人群的系统研究表明，基于GLP1的肥胖药物的疗效只需要后脑神经元。后脑GLP1R神经元的体内双光子成像表明，大多数神经元要么适应营养性刺激，要么适应厌恶性刺激，而不是同时适应营养刺激和厌恶刺激。

此外，后脑亚区的同步成像表明，后脑后区（AP）GLP1R神经元具有广泛的反应性，而孤束（NTS）GLP1R神经核则偏向于营养刺激。对这些群体的单独操纵表明，在没有厌恶的情况下，NTS^GLP1R神经元的激活会引发饱腹感，而AP^GLP1R神经元的活化会随着食物摄入量的减少而引发强烈的厌恶感。解剖学和行为学分析表明，NTS^GLP1R和AP^GLP1R神经元分别向不同的下游大脑区域发送投射，以驱动饱腹感和厌恶感。即使厌恶途径受到抑制，GLP1R激动剂也会减少食物摄入。

总之，这些发现强调了NTS^GLP1R神经元是一个可以选择性靶向促进减肥的群体，同时避免限制治疗依从性的副作用。

附：英文原文

Title: Dissociable hindbrain GLP1R circuits for satiety and aversion

Author: Huang, Kuei-Pin, Acosta, Alisha A., Ghidewon, Misgana Y., McKnight, Aaron D., Almeida, Milena S., Nyema, Nathaniel T., Hanchak, Nicholas D., Patel, Nisha, Gbenou, Yenoukoume S. K., Adriaenssens, Alice E., Bolding, Kevin A., Alhadeff, Amber L.

Issue&Volume: 2024-07-10

Abstract: The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

DOI: 10.1038/s41586-024-07685-6

Source: https://www.nature.com/articles/s41586-024-07685-6