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.
Highlights
Neurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein
Transgenes alone (Fig. 1d and Supplementary Fig. 1c). These findings suggest that the loss of Nf1 function elevates metabolic rate via neuronal mechanisms
The effect was smaller than the Nf1P1 mutant, suggesting that the neurons in the pyruvate carboxylase (PCB)-Gal[4] driver encompass part of the circuit/mechanism responsible for the effect. These results were significant regardless of whether incorporation was normalized to body weight or the number of flies (Supplementary Fig. 4). These findings suggest that energy stores and turnover kinetics are altered in Nf1 loss of function
Summary
Neurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. 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. We investigate the role of the Drosophila melanogaster NF1 ortholog in metabolic regulation This provides an excellent model for studying the fundamental biology of NF1 and the cellular/circuit effects associated with loss of Nf1 function. Flies with NF1 mutations exhibit small body size[14,15,16], impaired circadian rhythms[17], learning and memory deficits[18,19,20], decreased lifespan via increased susceptibility to oxidative stress[21], and increased spontaneous grooming[22,23] These changes demonstrate widespread alterations in cellular/neuronal function, raising the possibility that metabolism could be altered. We report that loss of Nf1 increases metabolic rate, feeding, and energy homeostasis via actions on a central neuronal circuit
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
