LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK
Objective: Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in hu...
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000043 |
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| author | Joanna Filipowska Zelda Cisneros Sneha S. Varghese Nancy Leon-Rivera Peng Wang Randy Kang Geming Lu Yate-Ching Yuan Hung-Ping Shih Supriyo Bhattacharya Sangeeta Dhawan Adolfo Garcia-Ocaña Nagesha Guthalu Kondegowda Rupangi C. Vasavada |
| author_facet | Joanna Filipowska Zelda Cisneros Sneha S. Varghese Nancy Leon-Rivera Peng Wang Randy Kang Geming Lu Yate-Ching Yuan Hung-Ping Shih Supriyo Bhattacharya Sangeeta Dhawan Adolfo Garcia-Ocaña Nagesha Guthalu Kondegowda Rupangi C. Vasavada |
| author_sort | Joanna Filipowska |
| collection | DOAJ |
| description | Objective: Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets. Although LGR4 has regenerative, anti-inflammatory, and anti-apoptotic effects in other tissues, its functional significance in β-cells remains unknown. We have previously identified Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) as a negative regulator of β-cell health. In this study, we assessed the regulation of Lgr4 in islets, and the role of LGR4 and LGR4/RANK stoichiometry in β-cell health under basal and stress-induced conditions, in vitro and in vivo. Methods: We evaluated Lgr4 expression in mouse and human islets in response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db mice, and aging) stress. To determine the role of LGR4 we employed in vitro Lgr4 loss and gain of function in primary rodent and human β-cells and examined its mechanism of action in the rodent INS1 cell line. Using Lgr4fl/fl and Lgr4fl/fl/Rankfl/fl × Ins1-Cre mice we generated β-cell-specific conditional knockout (cko) mice to test the role of LGR4 and its interaction with RANK in vivo under basal and stress-induced conditions. Results: Lgr4 expression in rodent and human islets was reduced by multiple stressors. In vitro, Lgr4 knockdown decreased proliferation and survival in rodent β-cells, while overexpression protected against cytokine-induced cell death in rodent and human β-cells. Mechanistically, LGR4 protects β-cells by suppressing RANK- Tumor necrosis factor receptor associated factor 6 (TRAF6) interaction and subsequent activation of NFκB. Lgr4cko mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased β-cell proliferation and maturation only in females. Male Lgr4cko mice under stress displayed reduced β-cell proliferation and a further increase in β-cell death. The impaired β-cell phenotype in Lgr4cko mice was rescued in Lgr4/Rank double ko (dko) mice. Upon aging, both male and female Lgr4cko mice displayed impaired β-cell homeostasis, however, only female mice became glucose intolerant with decreased plasma insulin. Conclusions: These data demonstrate a novel role for LGR4 as a positive regulator of β-cell health under basal and stress-induced conditions, through suppressing the negative effects of RANK. |
| format | Article |
| id | doaj-art-b6b53ba06a414df7be87e209a4b67ef1 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Molecular Metabolism |
| spelling | doaj-art-b6b53ba06a414df7be87e209a4b67ef12025-02-01T04:11:59ZengElsevierMolecular Metabolism2212-87782025-02-0192102097LGR4 is essential for maintaining β-cell homeostasis through suppression of RANKJoanna Filipowska0Zelda Cisneros1Sneha S. Varghese2Nancy Leon-Rivera3Peng Wang4Randy Kang5Geming Lu6Yate-Ching Yuan7Hung-Ping Shih8Supriyo Bhattacharya9Sangeeta Dhawan10Adolfo Garcia-Ocaña11Nagesha Guthalu Kondegowda12Rupangi C. Vasavada13Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USADiabetes, Obesity and Metabolism Institute, and Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Molecular and Cellular Endocrinology, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Molecular and Cellular Endocrinology, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Computational Quantitative Medicine, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Molecular Imaging and Therapy, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Molecular and Cellular Endocrinology, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USAArthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA 91010, USA; Corresponding author. Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Room 1131E3, Gonda North, 1500 E Duarte Road, Duarte, CA 91010, USA.Objective: Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets. Although LGR4 has regenerative, anti-inflammatory, and anti-apoptotic effects in other tissues, its functional significance in β-cells remains unknown. We have previously identified Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) as a negative regulator of β-cell health. In this study, we assessed the regulation of Lgr4 in islets, and the role of LGR4 and LGR4/RANK stoichiometry in β-cell health under basal and stress-induced conditions, in vitro and in vivo. Methods: We evaluated Lgr4 expression in mouse and human islets in response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db mice, and aging) stress. To determine the role of LGR4 we employed in vitro Lgr4 loss and gain of function in primary rodent and human β-cells and examined its mechanism of action in the rodent INS1 cell line. Using Lgr4fl/fl and Lgr4fl/fl/Rankfl/fl × Ins1-Cre mice we generated β-cell-specific conditional knockout (cko) mice to test the role of LGR4 and its interaction with RANK in vivo under basal and stress-induced conditions. Results: Lgr4 expression in rodent and human islets was reduced by multiple stressors. In vitro, Lgr4 knockdown decreased proliferation and survival in rodent β-cells, while overexpression protected against cytokine-induced cell death in rodent and human β-cells. Mechanistically, LGR4 protects β-cells by suppressing RANK- Tumor necrosis factor receptor associated factor 6 (TRAF6) interaction and subsequent activation of NFκB. Lgr4cko mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased β-cell proliferation and maturation only in females. Male Lgr4cko mice under stress displayed reduced β-cell proliferation and a further increase in β-cell death. The impaired β-cell phenotype in Lgr4cko mice was rescued in Lgr4/Rank double ko (dko) mice. Upon aging, both male and female Lgr4cko mice displayed impaired β-cell homeostasis, however, only female mice became glucose intolerant with decreased plasma insulin. Conclusions: These data demonstrate a novel role for LGR4 as a positive regulator of β-cell health under basal and stress-induced conditions, through suppressing the negative effects of RANK.http://www.sciencedirect.com/science/article/pii/S2212877825000043LGR4β-cell stressRANKNFκBβ-cell proliferationβ-cell death |
| spellingShingle | Joanna Filipowska Zelda Cisneros Sneha S. Varghese Nancy Leon-Rivera Peng Wang Randy Kang Geming Lu Yate-Ching Yuan Hung-Ping Shih Supriyo Bhattacharya Sangeeta Dhawan Adolfo Garcia-Ocaña Nagesha Guthalu Kondegowda Rupangi C. Vasavada LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK Molecular Metabolism LGR4 β-cell stress RANK NFκB β-cell proliferation β-cell death |
| title | LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK |
| title_full | LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK |
| title_fullStr | LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK |
| title_full_unstemmed | LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK |
| title_short | LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK |
| title_sort | lgr4 is essential for maintaining β cell homeostasis through suppression of rank |
| topic | LGR4 β-cell stress RANK NFκB β-cell proliferation β-cell death |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000043 |
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