(P26-072-25) Nobiletin Alleviated Npy1r-Mediated Insulin Secretion Deficiency of Islet β-Cells via the Clock-Modulatory Signaling

Objectives: The insufficient insulin secretion of β-cells plays a crucial role in the occurrence and development of type 2 diabetes. It is reported that this was associated with the overexpression of neuropeptide Y1 receptor (Npy1r) on β-cells due to the disorder of the neuropeptide Y (NPY) family peptides. Nobiletin (NOB), a natural flavonoid compound that acts as a circadian regulator and may potentially treat β-cells secretion impairment by downregulating the expression of Npy1r. Previous studies showed that Npy1r inhibitors improved fasting hyperglycemia in diabetes patients. The objective of this study was to investigate whether NOB mitigates Npyr1-induced secretory dysfunction in islet β-cells via the regulation of clock-modulatory signaling.

Methods: The effects of NOB on islet secretory function was evaluated using T2DM mouse models induced by a high-fat diet combined with low-dose streptozotocin, as well as hyperglycemic mouse models induced by NPY injection. In addition to assessing the effects of NOB on PA- or NPY-induced MIN6 cells, we also utilized MIN6 cells transfected with Bmal1::Luc to investigate the specific mechanism by which overexpressed Bmal1 regulates Npy1r expression in islet β-cells.

Results: We found that NOB alleviated the disorder of the NPY family peptides in diabetes mice. The molecular simulation results suggested that NOB interacted with Npy1r. Besides, NOB mitigated insufficient insulin secretion and hyperglycemia caused by Npy1r overexpression. Furthermore, NOB activated rhythmicity of β-cells via the RORs/Bmal1-Yap pathway in vitro, which may be one way through which NOB affects Npy1r expression. The function of β-cells is improved by NOB, which downregulates Npy1r expression both in vivo and in vitro.

Conclusions: Our research indicates that NOB may activate the circadian rhythm pathway and inhibit the Yap signal, thereby alleviating insulin secretion dysfunction of β-cells by suppressing the Npy1r signal.

Funding Sources: This study is supported by the Guangdong Provincial Key R&D Program [grant number 2022B0202030001], the Guangdong Basic and Applied Basic Research Foundation [grant number 2023A1515011065] and the Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program [grant number 2021TQ06N130].