Dysfunction of the gut-brain axis is one of the potential contributors to the pathophysiology of obesity and is therefore a potential target for treatment. Vagal afferents innervating the gut play an important role in controlling energy homeostasis. There is an increasing evidence for the role of vagal afferents in mediating the anorexigenic effects of glucagon-like peptide-1 (GLP-1), an important satiety and incretin hormone. This study aimed to examine the effect of chronic high fat diet on GLP-1 sensitivity in vagal afferents. C57/BL6 mice were fed either a high-fat or low-fat diet for 6–8 weeks. To evaluate gastrointestinal afferent sensitivity and nodose neurons’ response to GLP-1, extracellular afferent recordings and patch clamp were performed, respectively. Exendin-4 (Ex-4) was used as an agonist of the GLP-1 receptor. C-Fos Expression was examined as an indication of afferent input to the nucleus tractus solitarius (NTS). Food intake was monitored in real-time before and after Ex-4 treatment to monitor the consequence of the high fat diet on the satiating effect of GLP-1. In high fat fed (HFF) mice, GLP-1 caused lower activation of intestinal afferent nerves, and failed to potentiate mechanosensitive nerve responses compared to low fat fed (LFF). GLP-1 increased excitability in LFF and this effect was reduced in HFF neurons. Consistent with these findings on vagal afferent nerves, GLP-1 receptor stimulation given systemically, had a reduced satiating effect in HFF compared to LFF mice, and neuronal activation in the NTS was also reduced. The present study demonstrated chronic high fat diet impaired vagal afferent responses to GLP-1, resulting in impaired satiety signaling. GLP-1 sensitivity may account for the impairment of satiety signaling in obesity and thus a therapeutic target for obesity treatment.

肠脑轴功能障碍是肥胖症病理生理的潜在因素之一，因此是治疗的潜在靶标。支配肠的迷走神经传入在控制能量稳态中起重要作用。越来越多的证据表明迷走神经传入在介导胰高血糖素样肽1（GLP-1）（一种重要的饱腹感和肠降血糖素）的厌食作用中的作用。这项研究旨在检查慢性高脂饮食对迷走神经传入中GLP-1敏感性的影响。给C57 / BL6小鼠喂高脂或低脂饮食6-8周。为了评估胃肠道传入敏感性和结节神经元对GLP-1的反应，分别进行了细胞外传入记录和膜片钳。Exendin-4（Ex-4）用作GLP-1受体的激动剂。检查了C-Fos表达，作为对孤束核（NTS）的传入输入的指示。在Ex-4处理之前和之后实时监测食物摄入量，以监测高脂饮食对GLP-1饱腹感的影响。在高脂喂养（HFF）小鼠中，与低脂喂养（LFF）相比，GLP-1引起肠道传入神经的活化较低，并且未能增强机械敏感的神经反应。GLP-1增加了LFF的兴奋性，而这种作用在HFF神经元中减少了。与迷走神经传入的这些发现相一致，与LFF小鼠相比，全身给予GLP-1受体刺激对HFF的饱腹感降低，并且NTS中的神经元活化也降低了。本研究表明，慢性高脂饮食会损害迷走神经对GLP-1的传入反应，导致饱腹感信号受损。GLP-1敏感性可能是肥胖症中饱腹感信号受损的原因，因此是肥胖症治疗的治疗目标。