Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity
The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in viv...
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MDPI AG
2022-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/3/425 |
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| author | No-Joon Song Aejin Lee Rumana Yasmeen Qiwen Shen Kefeng Yang Shashi Bhushan Kumar Danah Muhanna Shanvanth Arnipalli Sabrena F. Noria Bradley J. Needleman Jeffrey W. Hazey Dean J. Mikami Joana Ortega-Anaya Rafael Jiménez-Flores Jeremy Prokop Ouliana Ziouzenkova |
| author_facet | No-Joon Song Aejin Lee Rumana Yasmeen Qiwen Shen Kefeng Yang Shashi Bhushan Kumar Danah Muhanna Shanvanth Arnipalli Sabrena F. Noria Bradley J. Needleman Jeffrey W. Hazey Dean J. Mikami Joana Ortega-Anaya Rafael Jiménez-Flores Jeremy Prokop Ouliana Ziouzenkova |
| author_sort | No-Joon Song |
| collection | DOAJ |
| description | The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in <i>Lep<sup>ob</sup></i> mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in <i>Lep<sup>ob</sup></i> mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of <i>Lep<sup>ob</sup></i> mice. EREG/LepR regulated glucose uptake without changes in obesity in <i>Lep<sup>ob</sup></i> mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in <i>Lepr<sup>db</sup></i> mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand. |
| first_indexed | 2024-03-10T00:04:02Z |
| format | Article |
| id | doaj.art-24d8b9ef3db24a0ea9410ea8d13beaab |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:04:02Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-24d8b9ef3db24a0ea9410ea8d13beaab2023-11-23T16:11:41ZengMDPI AGCells2073-44092022-01-0111342510.3390/cells11030425Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in ObesityNo-Joon Song0Aejin Lee1Rumana Yasmeen2Qiwen Shen3Kefeng Yang4Shashi Bhushan Kumar5Danah Muhanna6Shanvanth Arnipalli7Sabrena F. Noria8Bradley J. Needleman9Jeffrey W. Hazey10Dean J. Mikami11Joana Ortega-Anaya12Rafael Jiménez-Flores13Jeremy Prokop14Ouliana Ziouzenkova15Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USADivision of General and Gastrointestinal Surgery, Center for Minimally Invasive Surgery, The Ohio State University, Columbus, OH 43210, USADivision of General and Gastrointestinal Surgery, Center for Minimally Invasive Surgery, The Ohio State University, Columbus, OH 43210, USADepartment of Surgery, The Ohio State University, Columbus, OH 43210, USADepartment of Surgery, University of Hawaii, Honolulu, HI 96813, USADepartment of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USADepartment of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USADepartment of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USADepartment of Human Sciences, The Ohio State University, Columbus, OH 43210, USAThe leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in <i>Lep<sup>ob</sup></i> mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in <i>Lep<sup>ob</sup></i> mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of <i>Lep<sup>ob</sup></i> mice. EREG/LepR regulated glucose uptake without changes in obesity in <i>Lep<sup>ob</sup></i> mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in <i>Lepr<sup>db</sup></i> mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand.https://www.mdpi.com/2073-4409/11/3/425epiregulinleptin receptorERKEGFRglucose uptakeenergy metabolism |
| spellingShingle | No-Joon Song Aejin Lee Rumana Yasmeen Qiwen Shen Kefeng Yang Shashi Bhushan Kumar Danah Muhanna Shanvanth Arnipalli Sabrena F. Noria Bradley J. Needleman Jeffrey W. Hazey Dean J. Mikami Joana Ortega-Anaya Rafael Jiménez-Flores Jeremy Prokop Ouliana Ziouzenkova Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity Cells epiregulin leptin receptor ERK EGFR glucose uptake energy metabolism |
| title | Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity |
| title_full | Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity |
| title_fullStr | Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity |
| title_full_unstemmed | Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity |
| title_short | Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity |
| title_sort | epiregulin as an alternative ligand for leptin receptor alleviates glucose intolerance without change in obesity |
| topic | epiregulin leptin receptor ERK EGFR glucose uptake energy metabolism |
| url | https://www.mdpi.com/2073-4409/11/3/425 |
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