Nobiletin Alleviates Npy1r‐Mediated Insulin Secretion Deficiency of Islet β‐Cells via the Clock‐Modulatory Signaling

Current research indicates that insulin secretion deficiency in β‐cells contributes to Type 2 diabetes mellitus (T2DM), which is associated with neuropeptide Y1 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.