Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells
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
Affiliations
Paul V. Sabatini
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Thilo Speckmann
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Cuilan Nian
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Maria M. Glavas
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
Chi Kin Wong
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Ji Soo Yoon
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada
Tatsuya Kin
Department of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
A.M. James Shapiro
Department of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
William T. Gibson
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
C. Bruce Verchere
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
Francis C. Lynn
Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada; Corresponding author
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
