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Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Author

Listed:
  • Valentina Botero

    (The Scripps Research Institute, Scripps Florida)

  • Bethany A. Stanhope

    (Florida Atlantic University)

  • Elizabeth B. Brown

    (Florida Atlantic University)

  • Eliza C. Grenci

    (The Scripps Research Institute, Scripps Florida)

  • Tamara Boto

    (The Scripps Research Institute, Scripps Florida
    Trinity College Dublin)

  • Scarlet J. Park

    (The Scripps Research Institute, Scripps Florida)

  • Lanikea B. King

    (The Scripps Research Institute, Scripps Florida)

  • Keith R. Murphy

    (The Scripps Research Institute, Scripps Florida)

  • Kenneth J. Colodner

    (Mount Holyoke College)

  • James A. Walker

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Alex C. Keene

    (Florida Atlantic University)

  • William W. Ja

    (The Scripps Research Institute, Scripps Florida)

  • Seth M. Tomchik

    (The Scripps Research Institute, Scripps Florida)

Abstract

Neurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

Suggested Citation

  • Valentina Botero & Bethany A. Stanhope & Elizabeth B. Brown & Eliza C. Grenci & Tamara Boto & Scarlet J. Park & Lanikea B. King & Keith R. Murphy & Kenneth J. Colodner & James A. Walker & Alex C. Keen, 2021. "Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24505-x
    DOI: 10.1038/s41467-021-24505-x
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    References listed on IDEAS

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    1. Zhiguo Ma & Tobias Stork & Dwight E. Bergles & Marc R. Freeman, 2016. "Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour," Nature, Nature, vol. 539(7629), pages 428-432, November.
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