Cyclic neuronostatin regulates glucose homeostasis and food intake through GPR107 phosphorylation

Glucose homeostasis is vital for energy metabolism, and its dysregulation is central to metabolic diseases. To enhance the stability of the endogenous peptide neuronostatin (NST), we designed a conformationally stabilized cyclic NST peptide via disulfide-bridge cyclization. This study demonstrates that cyclic NST serves as a potent agonist for the G protein-coupled receptor 107 (GPR107), and promotes protein kinase activation. Intraperitoneal administration of cyclic NST induced sustained hyperglycemia, which was more effectively than linear NST, it also suppressed insulin and modulating leptin levels in zebrafish and mice. It differentially regulated glycolytic enzymes in pancreas and liver, and stimulated pancreatic α-cells to promote hepatic glucose production. Centrally, cyclic NST reduced food intake by activating the arcuate nucleus and the ventromedial hypothalamus. Notably, it upregulates the expression of key neuropeptides and receptors involved in appetite regulation, including the orexigenic peptides agouti-related protein (AgRP) and neuropeptide Y (NPY), as well as the anorexigenic peptide somatostatin, and the receptors gastric inhibitory polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R). Mechanistically, cyclic NST enhanced mitochondrial energy metabolism in a manner associated with phosphorylation-dependent Golgi retention of GPR107, with Tyr315 identified as a critical site for maintaining mitochondrial protein expression and regulating reactive oxygen species. Collectively, these findings establish the cyclic NST-GPR107 axis as a key regulator of glucose homeostasis and appetite, suggesting a novel therapeutic target for metabolic disorders.