Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

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. Keene, William W. Ja and Seth M. Tomchik ()
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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
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
Alex C. Keene: Florida Atlantic University
William W. Ja: The Scripps Research Institute, Scripps Florida
Seth M. Tomchik: The Scripps Research Institute, Scripps Florida

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24505-x

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