(3-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice

Objective: Notch signaling, re-activated in (3 cells from obese mice and causal to (3 cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that (3 cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice. Methods: We assessed expression of Notch pathway components in high-fat diet-fed (HFD) or leptin receptor-deficient (db/db) mice, and performed single-cell RNA sequencing (scRNA-Seq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, (3 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 HFD-fed and db/db mice, as well as in metabolicallyinflexible (3 cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from HFD-fed and db/db mice potentiated GSIS ex vivo. To demonstrate if (3 cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible (3 cell-specific Jag1 transgenic ((3-Jag1TG) and loss-of-function (i(3-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of (3 cell Jagged1 did not protect against HFD-induced insulin secretory defects. 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 (3 cells are not a likely source of the Jagged1 signal. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).