Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells
Summary: Depolarization of neuroendocrine cells results in calcium influx, which induces vesicle exocytosis and alters gene expression. These processes, along with the restoration of resting membrane potential, are energy intensive. We hypothesized that cellular mechanisms exist to maximize energy p...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717318429 |
| _version_ | 1818118394771144704 |
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| author | Paul V. Sabatini Thilo Speckmann Cuilan Nian Maria M. Glavas Chi Kin Wong Ji Soo Yoon Tatsuya Kin A.M. James Shapiro William T. Gibson C. Bruce Verchere Francis C. Lynn |
| author_facet | Paul V. Sabatini Thilo Speckmann Cuilan Nian Maria M. Glavas Chi Kin Wong Ji Soo Yoon Tatsuya Kin A.M. James Shapiro William T. Gibson C. Bruce Verchere Francis C. Lynn |
| author_sort | Paul V. Sabatini |
| collection | DOAJ |
| description | Summary: Depolarization of neuroendocrine cells results in calcium influx, which induces vesicle exocytosis and alters gene expression. These processes, along with the restoration of resting membrane potential, are energy intensive. We hypothesized that cellular mechanisms exist to maximize energy production during excitation. Here, we demonstrate that NPAS4, an immediate early basic helix-loop-helix (bHLH)-PAS transcription factor, acts to maximize energy production by suppressing hypoxia-inducible factor 1α (HIF1α). As such, knockout of Npas4 from insulin-producing β cells results in reduced OXPHOS, loss of insulin secretion, β cell dedifferentiation, and type 2 diabetes. NPAS4 plays a similar role in the nutrient-sensing cells of the hypothalamus. Its knockout here results in increased food intake, reduced locomotor activity, and elevated peripheral glucose production. In conclusion, NPAS4 is critical for the coordination of metabolism during the stimulation of electrically excitable cells; its loss leads to the defects in cellular metabolism that underlie the cellular dysfunction that occurs in metabolic disease. : Sabatini et al. show that NPAS4 is critical for coordination of cellular and organismal metabolism. Its loss contributes to the defects that underlie both islet and hypothalamic dysfunction, which result in the development of type 2 diabetes. Keywords: Npas4, Hif1α, Arnt, metabolism, diabetes, insulin, dedifferentiation, islets, hypothalamus, Pdx1CreER |
| first_indexed | 2024-12-11T04:53:37Z |
| format | Article |
| id | doaj.art-7b8849adfc394379875cec3389786339 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T04:53:37Z |
| publishDate | 2018-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7b8849adfc394379875cec33897863392022-12-22T01:20:20ZengElsevierCell Reports2211-12472018-01-01221163174Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine CellsPaul V. Sabatini0Thilo Speckmann1Cuilan Nian2Maria M. Glavas3Chi Kin Wong4Ji Soo Yoon5Tatsuya Kin6A.M. James Shapiro7William T. Gibson8C. Bruce Verchere9Francis C. Lynn10Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, CanadaDepartment of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, CanadaDepartment of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, CanadaDepartment of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, CanadaDiabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada; Corresponding authorSummary: Depolarization of neuroendocrine cells results in calcium influx, which induces vesicle exocytosis and alters gene expression. These processes, along with the restoration of resting membrane potential, are energy intensive. We hypothesized that cellular mechanisms exist to maximize energy production during excitation. Here, we demonstrate that NPAS4, an immediate early basic helix-loop-helix (bHLH)-PAS transcription factor, acts to maximize energy production by suppressing hypoxia-inducible factor 1α (HIF1α). As such, knockout of Npas4 from insulin-producing β cells results in reduced OXPHOS, loss of insulin secretion, β cell dedifferentiation, and type 2 diabetes. NPAS4 plays a similar role in the nutrient-sensing cells of the hypothalamus. Its knockout here results in increased food intake, reduced locomotor activity, and elevated peripheral glucose production. In conclusion, NPAS4 is critical for the coordination of metabolism during the stimulation of electrically excitable cells; its loss leads to the defects in cellular metabolism that underlie the cellular dysfunction that occurs in metabolic disease. : Sabatini et al. show that NPAS4 is critical for coordination of cellular and organismal metabolism. Its loss contributes to the defects that underlie both islet and hypothalamic dysfunction, which result in the development of type 2 diabetes. Keywords: Npas4, Hif1α, Arnt, metabolism, diabetes, insulin, dedifferentiation, islets, hypothalamus, Pdx1CreERhttp://www.sciencedirect.com/science/article/pii/S2211124717318429 |
| spellingShingle | Paul V. Sabatini Thilo Speckmann Cuilan Nian Maria M. Glavas Chi Kin Wong Ji Soo Yoon Tatsuya Kin A.M. James Shapiro William T. Gibson C. Bruce Verchere Francis C. Lynn Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells Cell Reports |
| title | Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells |
| title_full | Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells |
| title_fullStr | Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells |
| title_full_unstemmed | Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells |
| title_short | Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells |
| title_sort | neuronal pas domain protein 4 suppression of oxygen sensing optimizes metabolism during excitation of neuroendocrine cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717318429 |
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