Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Abstract

1Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of 2 features, the most characteristic of which include areas of abnormal skin pigmentation and 3 benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but 4 more serious symptoms also include malignant peripheral nerve sheath tumors, other 5 malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein 6 that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and 7 organismal function. Recent evidence suggests NF1 may regulate metabolism, though the 8 mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates 9 metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 10 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid 11 stores while increasing lipid turnover rate. The increase in metabolic rate is independent of 12 locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. 13The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, 14suggesting that increased feeding may be a compensatory effect driven by the increase in 15 metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of 16 neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream 17 of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic 18 rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may 19 represent a pathophysiological mechanism in NF1, and provide a platform for investigating the 20 cellular role of neurofibromin in metabolic homeostasis. 21

Neurofibromin 1 mediates sleep depth in Drosophila

“…This system uses indirect calorimetry to measure CO 2 release, while simultaneously measuring activity via counting infrared beam crosses (Fig 3A; Brown et al, 2022; Stahl et al, 2017). In agreement with previous findings, sleep was reduced in Nf1 P1 mutants in the SAMM system, and the total metabolic rate (VCO 2 ) was elevated during the day and the night compared to controls (Fig S5A,B; Botero et al, 2021). Similar effects were observed upon pan-neuronal knockdown of Nf1 (Fig S5C,D).…”

“…Studies in mammalian models have revealed a robust role for Nf1 in sleep and metabolic regulation, raising the possibility that they contribute to the complex systems in humans (Anastasaki et al, 2019; Tritz et al, 2021). In Nf1 -deficient Drosophila , metabolic rate is chronically elevated, sleep is shortened, and circadian rhythms are dysregulated in Nf1 mutants (Bai et al, 2018; Bai & Sehgal, 2015; Botero et al, 2021; King et al, 2016; Machado Almeida et al, 2021; Maurer et al, 2020; Williams et al, 2001), suggesting deep evolutionary conservation of Nf1 function. The findings that Nf1 plays a conserved role in regulating both sleep and metabolic rate raises the possibility that Nf1 is a critical integrator of these processes and that it may play a role in various forms of metabolic dysfunction that are associated with sleep disturbance (Arble et al, 2015; Depner et al, 2014).…”

“…In Drosophila and mammals, sleep is associated with reduced metabolic rate (Brown et al, 2022; Fontvieille et al, 1994; Stahl et al, 2017). In Drosophila , metabolic rate is elevated across the circadian cycle in Nf1 mutants, and this is associated with reductions in energy stores and starvation resistance (Botero et al, 2021). Here, we have applied indirect calorimetry to examine metabolic rate across individual sleep bouts and find that Nf1 is required for reductions in metabolic rate associated with prolonged time spent asleep.…”

Loss of NF1 causes tactile hypersensitivity and impaired synaptic transmission in a Drosophila model of autism spectrum disorder

“…Consequently, loss of NF1 leads to excessive Ras and diminished cAMP/PKA signalling (Bergoug et al, 2020). Moreover, levels of phosphorylated MAPK have been shown to be augmented in the NF1 P1 mutant, indicative of excessive Ras activity (Botero et al, 2021;Williams et al, 2001). Therefore, we investigated which of these biochemical functions, if either, might explain the role of NF1 in regulating synaptic transmission and larval mechanoreception.…”

Head circumference and anthropometric changes and their relation to plexiform and skin neurofibromas in sporadic and familial neurofibromatosis 1 Brazilian adults: a cross-sectional study

“…Altogether, these observations suggest that neurofibromin haploinsufficiency affects uptake, storage, and expenditure of energy [23,30,67]. In a recent study, Botero et al [68] showed that neurofibromin regulates metabolic homeostasis in Drosophila, increasing the metabolic rate, feeding, and energy homeostasis via actions on a central neuronal circuit.…”