The Vagus Nerve Mediates the Physiological but not Pharmacological Effects of PYY3-36 on Food Intake

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity mediated by the neuropeptide Y (NPY) Y2 receptor (Y2R). However, the neuronal pathways by which PYY3-36 acts to supress appetite are unclear. Determining how the PYY3-36 system physiologically regulates food intake may help exploit its therapeutic potential. Here we demonstrate that germline and post-natal targeted knockdown of the Y2R in the afferent vagus nerve inhibits the anorectic effects of physiologically-released PYY3-36, but not peripherally-administered higher doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is compensated for in the germline model. Loss of vagal Y2R signalling also alters meal patterning and accelerates gastric emptying. These results may facilitate the design of PYY-based anti-obesity agents.Abstract Figure

Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1β expression in the hypothalamus

Leptin is known to be an important circulating signal for regulation of food intake and body weight. Recent evidence has suggested that leptin is involved in infection and inflammation. The afferent vagus nerve is known to be an important component for transmitting peripheral immune signals to the brain, such as interleukin (IL)-1β expression in the brain, anorexia, and fever responses. In the present study, we investigated whether intravenous leptin-induced IL-1β expression in the hypothalamus is mediated via afferent vagus nerve. IL-1β transcripts in the hypothalamus were significantly increased on RT-PCR assessment 1 h after the administration of leptin (1 mg/kg iv) to mice. Subdiaphragmatic vagotomy did not significantly modify intravenous leptin-induced IL-1β expression in the hypothalamus compared with that in sham-treated mice. These data suggest that circulating leptin directly acts in the brain independently of afferent vagus nerve input originating from the subdiaphragmatic organs.

Electrical stimulation of afferent vagus nerve induces IL-1β expression in the brain and activates HPA axis

Possible roles of the afferent vagus nerve in regulation of interleukin (IL)-1β expression in the brain and hypothalamic-pituitary-adrenal (HPA) axis were examined in anesthetized rats. Levels of IL-1β mRNA and protein in the brain were measured by comparative RT-PCR and ELISA. Direct electrical stimulation of the central end of the vagus nerve was performed continuously for 2 h. The afferent stimulation of the vagus nerve induced increases in the expression of mRNA and protein levels of IL-1β in the hypothalamus and the hippocampus. Furthermore, expression of corticotropin-releasing factor mRNA was increased in the hypothalamus 2 h after vagal stimulation. Plasma levels of ACTH and corticosterone were also increased by this stimulation. The present results indicate that activation of the afferent vagus nerves itself can induce production of IL-1β in the brain and activate the HPA axis. Therefore, the afferent vagus nerve may play an important role in transmitting peripheral signals to the brain in the infection and inflammation.

Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1

Among proglucagon-derived peptides, the truncated form of glucagon-like peptide-1, GLP-1(7-36)amide (tGLP-1), is known as the most likely physiological humoral incretin. To examine whether there exists any relationship between tGLP-1 levels in the portal vein and activities of the hepatic and pancreatic vagal system, changes of the impulse discharge rate in the hepatic afferent vagus and the pancreatic efferent vagus upon intraportal tGLP-1 injection were measured in situ in rats anesthetized with urethan and chloralose. First, a 1-min bolus tGLP-1 injection at a periphysiological dose of 0.2 pmol or a pharmacological dose of 4.0 pmol, but not the vehicle injection, significantly facilitated the hepatic vagal afferents for > 90 min, showing weaker facilitation at the 0.05 pmol dose. Notably, the injection of noninsulinotropic full-length GLP-1 failed to facilitate the afferents at the 4.0 or 40.0 pmol dose. Second, the intraportal tGLP-1 injections at the 0.05 and 0.2 pmol dose facilitated marginally and significantly the pancreatic vagal efferents in normal rats, respectively, but had no effect on the hepatic vagotomized rats, even at the 40.0 pmol dose. The present results indicate that an intraportal appearance of tGLP-1 is specifically recognized by the hepatic vagal nerve, and this recognition further augments the pancreatic vagal efferent activity in a reflex way, suggesting another nature of tGLP-1 as neuroincretin in the enteroinsular axis.