The two wandering (latin: vagare) vagal nerves are the longest nerves of the parasympathetic nervous system, reaching from the vagal nuclei in the medulla to the colon, straying in the entire abdominal cavity. The nerves possess more afferent than efferent fibres, depending on species and their location—subdiaphragmatic and cervical parts. The neurons of the afferent fibres are located in the jugular and nodose ganglions (NG), projecting to the nuclei tractus solitarii (NTS). The current techniques to dissect the gastrointestinal vagal afferents and their functions have recently been reviewed by Wang et al¹ The afferent vagal fibres serve as important communication lines in the gut‐brain axis and participate in the control of food intake, for example, by peptides released from the gastrointestinal mucosa in response to nutrients. Using single cell RNA sequencing of the neurons of mice NG, Bai et al, reported that food intake is most sensitive to stimulation of the mechanoreceptors in the intestine.² Furthermore, it has previously been shown that cholecystokinin (CCK) inhibits food intake via afferent neurons in the NG,³ yet it has been unclear, whether this inhibition is short‐ or long term.

In this issue, McDougle and colleagues investigated, whether vagal afferent signalling from the gut plays a role in the long‐term regulation of energy balance using injections of the neurotoxin saporin conjugated to CCK into the NG of rats.⁴ Saporin (SAP) conjugated CCK (CCK‐SAP) was injected into both NG and ablated neurons expressing CCK receptors. Conjugated SAP showed an approximately 80% reduction of the sensory neurons innervating the proximal gut.¹ The group has previously shown that these neurons innervate the mucosa and muscular layers of the stomach and the upper part of the small intestine. McDougle et al found that CCK‐SAP treatment in rats significantly decreased meal size with an increase in meal number, but no change in weekly normal chow intake, glucose tolerance, energy expenditure and weight gain was observed.⁴ Under a high fat diet challenge starting 6 weeks post‐SAP or CCK‐SAP treatments, CCK‐SAP‐treated rats significantly increased food intake, meal size and frequency, resulting in a higher weight gain over the 5‐week observation period compared to SAP‐treated control rats. Intraperitoneal glucose tolerance tests did not differ between the groups, indicating that the directly stimulated insulin release from the β cells was not impaired. Unfortunately, an oral glucose tolerance test was not performed. The authors carefully repeated their experiments at a different interval (11 weeks post injection) on normal chow before switching to 5‐week high fat chow challenge with similar results to exclude any changes in the afferent signalling over time. In addition, the authors investigated the response of intragastrically infused (fasted overnight at light onset, 10 mL at 1 mL/min 30 minutes before refeeding) 37.5% fat or 75% sucrose or 2% methylcellulose (control) on 12 hours food intake. SAP‐treated rats reduced food intake after sucrose and lipid infusion, while CCK‐SAP‐treated rats did not reduce their food intake after fat infusion, while sucrose infusion did, indicating a reduction in lipid sensing in the CCK‐SAP‐treated rats. In addition, no difference was found in an oral licking test of equicaloric solutions of 10% fat or 20% sucrose between the treated SAP‐ and CCK‐SAP‐treated rats, suggesting that changes in palatability were not the reason for the increased food intake under high fat diet. Yet, macronutrients in food affect also reward systems in the brain. Recently, Han et al, demonstrated in very elegant series of experiments using optogenetic tools that the right but not the left vagal sensory ganglion is important for mediation of gut induced rewards with an induction of dopamine release form the substantia nigra.⁵ CCK‐induced dopamine release in the dorsal striatum and substantia nigra lesions abolished the suppressive effects of CCK on food intake, indicating that reward circuits are involved in CCK‐mediated signalling, which is stimulated by fat.

McDougle et al⁴ demonstrate that CCK expressing neurons in the NG are important in long‐term weight control but only under high fat diet. In the jugular and nodose ganglia, multiple peptide receptors like leptin, cocaine‐ and amphetamine‐regulated transcript (CART), orexin‐1, ghrelin, galanin, peptide YY (PYY), glucagon like peptide (GLP1/2), GABA‐B, dopamine D2, nicotinic, cannabinoid, and bradykinin and calcitonin gene‐related peptide (CGRP, more in human than rat neurons) are expressed. Kupari and colleagues performed single cell sequencing technology of isolated neurons from the NG and identified by their receptor expression 18 distinct subtypes of neurons for serotonin, CCK, PYY and fatty acids, but not for example, ghrelin, leptin or GLP‐1, underscoring the heterogeneity of the vagal afferent neurons.⁶ We look forward to understanding, which neurons survived the CCK‐SAP treatment and for example, use SAP coupling to different peptide ligands to evaluate subsequently or additively their effects. Knockdown of GLP‐1 receptors by injection of lentiviral vector (LV), delivering a short hairpin (sh) RNA construct targeting the GLP‐1R mRNA transcript, bilaterally into the NG caused an increase in meal size with decrease in meal numbers and an accelerated gastric emptying, but did not affect long‐term energy balance under normal chow diet.⁷ Possible changes in gastric motility were not evaluated by McDougle et al.⁴

Under normal chow with 22.5% protein, 5.2% fat and 42.7% carbohydrates there was no difference in weight gain between SAP and CCK‐SAP treated rats⁴—the smaller meals were compensated for by an increased frequency. It is known that the increase from 5.2% to 45% of fat alters the sensitivity of the NG neurons to tension, peptide hormones and nutrients with probable changes in receptor expression and peptide release as discussed by McDougle et al.⁴ The recommended composition of macronutrients for humans are 20%‐35% fat, 10%‐35% protein and 45%‐65% carbohydrate of total energy intake, but in popular diets this can differ from 10% fat, 20% protein, 70% carbohydrate to 70% fat, 20% protein and 10% carbohydrates. The extreme comparison between a 5.2% fat towards a 45% fat chow makes the translation to the human situation quite challenging.

Chronic vagal nerve stimulation (VNS) is a treatment option for refractory epilepsy and depression. VNS results in weight loss, yet mostly the left vagal nerve is being used to minimize cardiac side effects. Surgical vagotomy is sometimes performed during bariatric surgery in the Roux‐en‐Y gastric bypass (RYGB) or during laparoscopic adjustable gastric banding (LAGB), yet the data of these effects on additional weight loss are limited and so far inconclusive.

The results of McDougle et al,⁴ substantially add to our knowledge about vagal afferents in promoting lipid‐mediated satiation, by providing evidence that CCK receptor expressing vagal sensory neurons are necessary for the prevention of excessive overconsumption of fat, inhibiting overeating and weight gain.

两条迷路的迷走神经是副交感神经系统中最长的神经，从延髓的迷走神经核到达结肠，在整个腹腔中散布。神经具有比传入纤维更多的传入纤维，具体取决于种类和它们的位置-ph下和颈椎部位。传入纤维的神经元位于颈神经节和结节神经节（NG），突出至孤束核（NTS）。Wang等[ ^1]最近综述了解剖胃肠道迷走神经传入及其功能的技术。传入迷走神经纤维是肠脑轴上的重要交流通道，并通过例如响应营养物从胃肠粘膜释放的肽参与食物摄入的控制。Bai等人使用小鼠NG神经元的单细胞RNA测序报道，食物摄入对肠中机械感受器的刺激最敏感。²此外，以前已经证明胆囊收缩素（CCK）通过NG中的传入神经元抑制食物摄入，³但目前尚不清楚这种抑制作用是短期还是长期的。

在本期中，McDougle及其同事研究了通过将与CCK偶联的神经毒素皂素注射到大鼠NG中，肠道的迷走神经传入信号是否在能量平衡的长期调节中发挥作用。^将4种Saporin（SAP）偶联的CCK（CCK-SAP）注射到表达CCK受体的NG和消融神经元中。共轭SAP显示支配近端肠道的感觉神经元减少约80％。^1个该小组先前已经证明，这些神经元支配着胃和小肠上部的粘膜和肌肉层。McDougle等人发现，在大鼠中进行CCK-SAP处理后，随着进食次数的增加，进食量显着减小，但每周正常食物摄入量，葡萄糖耐量，能量消耗和体重增加均未见变化。⁴在SAP或CCK-SAP治疗后6周开始的高脂饮食挑战下，与SAP相比，CCK-SAP治疗的大鼠显着增加了食物摄入，进餐量和进食频率，因此在5周观察期内体重增加更高治疗的对照大鼠。两组之间的腹膜内葡萄糖耐量试验没有差异，表明直接刺激的胰岛素从β细胞的释放没有受到损害。不幸的是，没有进行口服葡萄糖耐量试验。作者切换到5周高脂食物挑战后，在正常食物上以不同的间隔（注射后11周）仔细地重复了他们的实验，结果相似，以排除传入信号随时间的任何变化。此外，作者研究了在灌胃12小时后，灌胃（轻度禁食过夜，以1 mL / min的速度灌胃10 mL，再喂食前30分钟）对37.5％脂肪或75％蔗糖或2％甲基纤维素（对照组）的反应。用SAP处理的大鼠减少了蔗糖和脂质输注后的食物摄入量，而使用CCK-SAP处理的大鼠没有减少脂肪注入后的进食量，而使用蔗糖输注了食物，这表明CCK-SAP处理的大鼠中脂质感应的降低。此外，在经处理的SAP和CCK-SAP处理的大鼠之间的10％脂肪或20％蔗糖等热量溶液的口舔试验中，没有发现差异，这表明适口性的改变并不是食物摄入量增加的原因在高脂饮食下。然而，食物中的大量营养素也会影响大脑的奖赏系统。最近，Han等人，⁵ CCK诱导的背侧纹状体和黑质病变中的多巴胺释放消除了CCK对食物摄入的抑制作用，这表明奖励电路参与了CCK介导的信号传导，该信号被脂肪刺激。

McDougle等[ ^4]证明NG中CCK表达的神经元在长期体重控制中很重要，但仅在高脂饮食下才重要。在颈神经节和结节神经节中，多种肽受体如瘦素，可卡因和苯丙胺调节的转录物（CART），orexin-1，ghrelin，甘丙肽，YY肽（PYY），胰高血糖素样肽（GLP1 / 2），GABA-B ，多巴胺D2，烟碱，大麻素，缓激肽和降钙素基因相关肽（CGRP，在人中比在大鼠神经元中表达更多）被表达。Kupari及其同事进行了从NG分离出的神经元的单细胞测序技术，并通过其受体表达鉴定了血清素，CCK，PYY和脂肪酸的18种不同亚型的神经元，但没有，例如生长素释放肽，瘦素或GLP-1，强调了迷走神经传入神经元的异质性。⁶我们期待了解，哪些神经元在CCK-SAP处理中幸存下来，例如，将SAP与不同的肽配体偶联以评估其后作用或相加作用。通过注射慢病毒载体（LV）敲低GLP-1受体，向G两侧传递靶向GLP-1R mRNA转录物的短发夹（sh）RNA构建体，导致进餐量增加，进餐量减少并加速胃排空，但不影响正常饮食饮食下的长期能量平衡。⁷ McDougle等人未评估胃动力的可能变化。⁴

在蛋白质含量为22.5％，脂肪含量为5.2％，碳水化合物含量为42.7％的正常食物下，SAP和CCK-SAP处理的大鼠⁴的体重增加没有差异-较少的进餐可以通过增加频率来补偿。众所周知，从5.2％的脂肪增加到45％的脂肪会改变NG神经元对张力，肽激素和营养的敏感性，并可能改变受体表达和肽释放，如McDougle等人所讨论。⁴推荐给人体的大量营养素成分是总能量摄入的20％-35％脂肪，10％-35％蛋白质和45％-65％碳水化合物，但是在流行的饮食中，这可能不同于10％脂肪，20％蛋白质，70 ％的碳水化合物到70％的脂肪，20％的蛋白质和10％的碳水化合物。5.2％的脂肪与45％的脂肪的极端对比使得转换为人类情况颇具挑战性。

慢性迷走神经刺激（VNS）是难治性癫痫和抑郁症的治疗选择。VNS导致体重减轻，但大多数使用迷走神经是为了最大程度地减少心脏副作用。有时在Roux-en-Y胃旁路术（RYGB）的减肥手术中或在腹腔镜可调胃绑扎术（LAGB）期间进行手术迷走神经切断术，但这些影响额外减肥的数据仍然有限，目前尚无定论。

McDougle等人[ ^4]的结果通过提供证据表明表达CCK受体的迷走神经感觉神经元对于预防脂肪过度消耗，抑制暴饮暴食和体重增加是必要的，从而大大增加了我们对迷走神经传入促进脂质介导的饱足的认识。