BMS-193885

C-type natriuretic peptide (CNP), belonging to the natriuretic peptide group, has recently emerged as a potential modulator of feeding behavior in mammalian species. This study aimed to examine the impact of central infusion of CNP-22 on feeding behavior in neonatal broilers and to elucidate its interaction with the dopaminergic, malanocortinergic, and neuropeptide Y (NPY) systems. Across ten separate experiments, broilers were systematically allocated into four different treatment groups for each experiment. In the initial experiment, neonatal chickens (Ross-308) received ICV injections of saline or CNP-22 at escalating doses (0.75, 1.5, and 3 nmol). Subsequent experiments assessed the interplay between CNP-22 (3 nmol); L-DOPA, a precursor of dopamine; 6-hydroxydopamine (6-OHDA), a neurotoxin targeting dopaminergic neurons; SCH23390, an antagonist of D1 dopamine receptors; AMI-193, an antagonist of D2 dopamine receptors; SHU9119, an antagonist of melanocortin 3 and 4 receptors; HS 024, a selective melanocortin 4 receptor antagonist; BMS193885, an antagonist of the neuropeptide Y1 receptor; CYM9484, an antagonist of the neuropeptide Y2 receptor; and L-152,804, which functions as an antagonist at neuropeptide Y5 receptors. Treatments included individual injections and simultaneous co-administrations of CNP-22 with these pharmacological agents. Feed consumption was measured for 120 min post-infusion. When CNP-22 was administered at concentrations of 1.5 and 3 nmol, a progressive decline in meal consumption was observed, correlating with increasing dosage (P < 0.05). Co-infusion of BMS193885 + CNP-22 enhanced the anorexigenic effect induced by CNP-22 (P < 0.05). However, simultaneous infusion of 6-OHDA, SCH23390, and SHU9119 with CNP-22 markedly decreased CNP-22-induced anorexia (P < 0.05). The data indicate that CNP-22 administration suppresses feeding behavior in young broiler chickens, a process potentially mediated via the D1, MC3/MC4, and NPY1 receptors pathways.

Current research indicates that insulin secretion deficiency in β‐cells contributes to Type 2 diabetes mellitus (T2DM), which is associated with neuropeptide Y 1 receptor (Npy1r) overexpression from neuropeptide Y (NPY) system dysregulation. To date, limited literature has explored nobiletin (NOB) as a circadian modulator for restoring β‐cell function through Npy1r regulation. This study investigates NOB's stimulatory effects on insulin secretion via Npy1r and clock‐modulatory signaling to elucidate its underlying mechanism. The findings demonstrated that NOB ameliorated hyperglycemia and promoted insulin secretion in two distinct mouse models: T2DM induced by a high‐fat diet with low‐dose streptozotocin, and acute hyperglycemia triggered by NPY. Moreover, NOB reduced NPY family peptides in the serum and suppressed Npy1r overexpression in β‐cells. Comprehensive investigations revealed that NOB mitigated Npy1r‐mediated β‐cell dysfunction through activating clock‐modulatory signaling, evidenced by restored Bmal1::Luc bioluminescence rhythmicity in mouse insulinoma6 (MIN6) cells. Molecular docking confirmed a direct NOB‐Npy1r interaction, while mechanistic analyses demonstrated modulation of the retinoic acid‐related orphan receptors (RORs)/Bmal1‐Yes‐associated protein (Yap) pathway via Yap suppression and Bmal1 activation, based on the interventions with palmitic acid, BMS 193885 (Npy1r antagonist), and NPY. Therefore, this study provides evidence that NOB can protect β‐cells from insulin secretion dysfunction by downregulating Npy1r expression and activating the RORs/Bmal1‐Yap pathway.