The hypothalamic mechanism of neuropeptide S-induced satiety in Japanese quail (Coturnix japonica) involves the paraventricular nucleus and corticotropin-releasing factor.

Neuropeptide S (NPS), a 20-amino acid neuropeptide, is produced in the brain and is associated with appetite suppression.Our group was the first to report this anorexigenic effect in birds using chicken as a model, although a hypothalamic molecular mechanism remains to be elucidated. Thus, we designed the present study using Japanese quail(Coturnix japonica).In Experiment 1, quail intracerebroventricularly injected with NPS reduced both food and water intake. In Experiment 2, food-restricted quail injected with NPS displayed a reduction in water intake.In Experiment 3, NPS-injected quail reduced their feeding and exploratory pecks.In Experiment 4, we quantified the number of cells expressing the early intermediate gene product c-Fos (as a marker of neuronal activation) in appetite associated hypothalamic nuclei and found that immunoreactivity was increased in the paraventricular nucleus (PVN). In Experiment 5, we utilized real-time PCR to screen for neuropeptide changes within the PVN of NPS-injected quail. Mesotocin and corticotropin-releasing factor (CRF) mRNAs increased in response to NPS injection. In Experiment 6, co-injection of astressin, a CRF receptor antagonist, was sufficient to block the food intake-suppressive effects of NPS, but in Experiment 7, co-injection of an oxytocin receptor antagonist was not sufficient to block the food intake-suppressive effects of NPS. Collectively, results support that NPS induces an anorexigenic response in Japanese quail that is mediated within the PVN and is associated with CRF.

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety.

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide's satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.