孤束核中胰高血糖素样肽-1受体的激活可降低食物奖赏行为,并作用于中脑边缘系统。

Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system.

作者信息

Richard Jennifer E, Anderberg Rozita H, Göteson Andreas, Gribble Fiona M, Reimann Frank, Skibicka Karolina P

机构信息

Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

MRC Metabolic Diseases Unit and Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

出版信息

PLoS One. 2015 Mar 20;10(3):e0119034. doi: 10.1371/journal.pone.0119034. eCollection 2015.

Abstract

The gut/brain peptide, glucagon like peptide 1 (GLP-1), suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS), GLP-1 receptors (GLP-1R). Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

摘要

肠/脑肽胰高血糖素样肽1(GLP-1)通过作用于位于调节能量平衡的关键中枢神经系统区域(下丘脑或后脑)的受体来抑制食物摄入。此外,GLP-1可通过作用于其边缘系统受体来减少食物带来的奖赏及获取食物的动机。这些数据共同表明GLP-1在稳态和奖赏效应之间存在神经解剖学上的分离。在此,我们旨在挑战这一观点,并提出假说:GLP-1可通过直接作用于后脑孤束核(NTS)的GLP-1受体(GLP-1R)来调节食物奖赏行为。利用两种食物奖赏模型,即大鼠蔗糖渐进比率操作性条件反射和食物条件性位置偏爱,我们发现向NTS内微量注射GLP-1或其稳定类似物艾塞那肽-4可抑制食物奖赏行为。当大鼠在美味食物和普通食物之间进行选择时,向NTS内注射艾塞那肽-4优先减少了美味食物的摄入量,但对普通食物摄入量没有影响。然而,如果仅提供普通食物,激活NTS的GLP-1R会减少普通食物摄入量和体重。激活NTS的GLP-1不会改变一般运动活动,也不会通过条件性位置偏爱实验(PICA)诱导恶心。我们进一步表明,GLP-1纤维与NTS去甲肾上腺素能神经元紧密相邻,先前研究表明这些神经元在NTS和边缘系统之间提供单突触连接。中枢GLP-1R激活还增加了多巴胺-β-羟化酶(去甲肾上腺素合成中的关键酶)在NTS中的表达,表明这两个系统之间存在生物学联系。此外,激活NTS的GLP-1R改变了腹侧被盖区多巴胺相关基因的表达。这些数据揭示了NTS的GLP-1R具有抑制食物奖赏的作用,并表明食物奖赏控制的神经生物学靶点不仅限于边缘系统,而是分布于整个中枢神经系统。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/064b/4368564/d0e8dfe54f1f/pone.0119034.g001.jpg

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