Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development
Objective: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis an...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877816303131 |
| _version_ | 1811300433572921344 |
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| author | Lynda Elghazi Manuel Blandino-Rosano Emilyn Alejandro Corentin Cras-Méneur Ernesto Bernal-Mizrachi |
| author_facet | Lynda Elghazi Manuel Blandino-Rosano Emilyn Alejandro Corentin Cras-Méneur Ernesto Bernal-Mizrachi |
| author_sort | Lynda Elghazi |
| collection | DOAJ |
| description | Objective: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis. Method: Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors. Results: We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells. Conclusion: Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia. Keywords: Nutrients, mTOR, Rapamycin, Pancreas, Development, Islets, β-cells |
| first_indexed | 2024-04-13T06:51:05Z |
| format | Article |
| id | doaj.art-2cf8038ec3b7439e8b8d72afbae86ca0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-13T06:51:05Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-2cf8038ec3b7439e8b8d72afbae86ca02022-12-22T02:57:23ZengElsevierMolecular Metabolism2212-87782017-06-0166560573Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors developmentLynda Elghazi0Manuel Blandino-Rosano1Emilyn Alejandro2Corentin Cras-Méneur3Ernesto Bernal-Mizrachi4University of Michigan in Ann Arbor, Internal Medicine Department, MEND Division, Ann Arbor, MI, USAUniversity of Miami Miller School of Medicine and Miami VA Health Care System, Division of Endocrinology, Diabetes and Metabolism, Miami, FL, USAUniversity of Michigan in Ann Arbor, Internal Medicine Department, MEND Division, Ann Arbor, MI, USA; University of Minnesota, Department of Integrative Biology & Physiology, Minneapolis, MN, USAUniversity of Michigan in Ann Arbor, Internal Medicine Department, MEND Division, Ann Arbor, MI, USAUniversity of Miami Miller School of Medicine and Miami VA Health Care System, Division of Endocrinology, Diabetes and Metabolism, Miami, FL, USA; Corresponding author. Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine and Miami VA Health Care System, USA. Fax: +1 (305) 243 4039.Objective: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis. Method: Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors. Results: We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells. Conclusion: Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia. Keywords: Nutrients, mTOR, Rapamycin, Pancreas, Development, Islets, β-cellshttp://www.sciencedirect.com/science/article/pii/S2212877816303131 |
| spellingShingle | Lynda Elghazi Manuel Blandino-Rosano Emilyn Alejandro Corentin Cras-Méneur Ernesto Bernal-Mizrachi Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development Molecular Metabolism |
| title | Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development |
| title_full | Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development |
| title_fullStr | Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development |
| title_full_unstemmed | Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development |
| title_short | Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development |
| title_sort | role of nutrients and mtor signaling in the regulation of pancreatic progenitors development |
| url | http://www.sciencedirect.com/science/article/pii/S2212877816303131 |
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