Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

• Published in: Nature communications Vol. 12; no. 1; p. 4285
• Main Authors: Botero, Valentina, Stanhope, Bethany A., Brown, Elizabeth B., Grenci, Eliza C., Boto, Tamara, Park, Scarlet J., King, Lanikea B., Murphy, Keith R., Colodner, Kenneth J., Walker, James A., Keene, Alex C., Ja, William W., Tomchik, Seth M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 14/19; 631/378; 631/378/1689; 631/378/3920; 631/443/319/1488; 631/443/319/2723; 64/24; 82/80; 96/35; 96/63; Circuits; Drosophila; Fruit flies; Gene mapping; Genetic disorders; Homeostasis; Humanities and Social Sciences; Insects; Lipids; Locomotor activity; Metabolic rate; Metabolism; multidisciplinary; Mutation; Neurofibromatosis; Neurofibromin 1; Neurological disorders; Neurons; Protein turnover; Recklinghausen's disease; Science; Science (multidisciplinary); Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24505-x

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.
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in neurofibromin and associated with disruptions in physiology and behavior. Here the authors show that neurofibromin regulates metabolic homeostasis via a discrete brain circuit in a Drosophila model of NF1.