β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice
Objective: Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin se...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824000255 |
| _version_ | 1797272476643753984 |
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| author | Nina Suda Alberto Bartolomé Jiani Liang Jinsook Son Yoko Yagishita Christian Siebel Domenico Accili Hongxu Ding Utpal B. Pajvani |
| author_facet | Nina Suda Alberto Bartolomé Jiani Liang Jinsook Son Yoko Yagishita Christian Siebel Domenico Accili Hongxu Ding Utpal B. Pajvani |
| author_sort | Nina Suda |
| collection | DOAJ |
| description | Objective: Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β 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, β 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 metabolically-inflexible β 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 β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic (β-Jag1TG) and loss-of-function (iβ-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of β 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 β cells are not a likely source of the Jagged1 signal. |
| first_indexed | 2024-03-07T14:28:54Z |
| format | Article |
| id | doaj.art-3e7e5ec93dc1485189fc1b20f33fec79 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-07T14:28:54Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-3e7e5ec93dc1485189fc1b20f33fec792024-03-06T05:26:41ZengElsevierMolecular Metabolism2212-87782024-03-0181101894β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese miceNina Suda0Alberto Bartolomé1Jiani Liang2Jinsook Son3Yoko Yagishita4Christian Siebel5Domenico Accili6Hongxu Ding7Utpal B. Pajvani8Department of Medicine, Columbia University, New York, NY, USADepartment of Medicine, Columbia University, New York, NY, USADepartment of Medicine, Columbia University, New York, NY, USADepartment of Medicine, Columbia University, New York, NY, USADepartment of Medicine, Columbia University, New York, NY, USADepartment of Discovery Oncology, Genentech, South San Francisco, CA, USADepartment of Medicine, Columbia University, New York, NY, USADepartment of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USADepartment of Medicine, Columbia University, New York, NY, USA; Corresponding author. Columbia University Medical Center, Russ Berrie Science Pavilion, 1150 St, Nicholas Avenue, New York, NY 10032, USA.Objective: Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β 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, β 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 metabolically-inflexible β 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 β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic (β-Jag1TG) and loss-of-function (iβ-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of β 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 β cells are not a likely source of the Jagged1 signal.http://www.sciencedirect.com/science/article/pii/S2212877824000255NotchJagged1Beta cellAlpha cellInsulin secretionDiabetes |
| spellingShingle | Nina Suda Alberto Bartolomé Jiani Liang Jinsook Son Yoko Yagishita Christian Siebel Domenico Accili Hongxu Ding Utpal B. Pajvani β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice Molecular Metabolism Notch Jagged1 Beta cell Alpha cell Insulin secretion Diabetes |
| title | β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice |
| title_full | β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice |
| title_fullStr | β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice |
| title_full_unstemmed | β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice |
| title_short | β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice |
| title_sort | β cell jagged1 is sufficient but not necessary for islet notch activity and insulin secretory defects in obese mice |
| topic | Notch Jagged1 Beta cell Alpha cell Insulin secretion Diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824000255 |
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