ß-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.
Objective Notch signaling is re-activated in  ß cells from obese mice, and is causal to ß cell dysfunction. Notch activity is determined in part by expression of transmembrane ligand availability in a neighboring cell. We hypothesized that ß cell expression of Jagged1 determines the maladaptive Notch response and resultant ß cell dysfunction in obese mice. Methods We assessed expression of Notch pathway components in diet-induced obese (DIO) or leptin receptor-deficient (db/db) mice, and performed single cell RNA sequencing (scRNAseq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, ß cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets. Results Jag1 was the only Notch ligand that tracked with increased Notch activity in DIO and db/db mice. Consistently, JAG1 tracked with Notch activity in metabolically inflexible ß cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from DIO and db/db mice potentiated GSIS ex vivo. To demonstrate if ß cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible ß cell-specific Jag1 transgenic mice (ß-Jag1TG), which showed impaired glucose intolerance due to reduced GSIS. However, ß cell-specific Jagged1 loss-of-function (ß-Jag1KO) did not protect against HFD-induced insulin secretory defects or glucose intolerance. Conclusions Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that ß cells are not a likely source of the Jagged1 signal. Overall design: RNA-seq of pancreatic islets from ß cell Jag1-gain of function model