GWAS reveal a role for the central nervous system in regulating weight and weight change in response to exercise

Abstract

Body size and weight show considerable variation both within and between species. This variation is controlled in part by genetics, but also strongly influenced by environmental factors including diet and the level of activity experienced by the individual. Due to the increasing obesity epidemic in much of the world, there is considerable interest in the genetic factors that control body weight and how weight changes in response to exercise treatments. Here, we address this question in the Drosophila model system, utilizing 38 strains of the Drosophila Genetics Reference Panel. We use GWAS to identify the molecular pathways that control weight and weight changes in response to exercise. We find that there is a complex set of molecular pathways controlling weight, with many genes linked to the central nervous system (CNS). The CNS also plays a role in the weight change with exercise, in particular, signaling from the CNS. Additional analyses revealed that weight in Drosophila is driven by two factors, animal size, and body composition, as the amount of fat mass versus lean mass impacts the density. Thus, while the CNS appears to be important for weight and exercise-induced weight change, signaling pathways are particularly important for determining how exercise impacts weight.

Sex determination gene transformer regulates the male-female difference in Drosophila fat storage via the adipokinetic hormone pathway

“…This suggests additional metabolic genes and pathways must contribute to sex differences in fat storage and breakdown ( Wat et al, 2020 ). Indeed, genome-wide association studies in Drosophila demonstrate sex-biased effects on fat storage for many genetic loci ( Nelson et al, 2016 ; Watanabe and Riddle, 2021 ). As evidence of sex-specific mechanisms underlying whole-body fat storage continues to mount, several reports have also identified male-female differences in phenotypes linked with fat metabolism.…”

Exercise-induced changes in climbing performance

“…This finding is confirmed using the lifespan data from Ivanov and colleagues [37] (Pearson's product-moment correlation r = −0.065, p = 0.7202). Similarly, when we investigate the relationship between animal weight and climbing ability (data from [32]), we find no significant correlation in either sex, in control or exercise-treated animals (Pearson's product-moment correlation, p > 0.4). These findings suggest that high physical fitness, as measured by a climbing index, is not linked to either lifespan or animal weight in these Drosophila strains.…”

“…We have shown that exercise induction with the TreadWheel leads to changes in activity levels in a sex-and genotype-dependent manner [31]. A 5-day exercise treatment with the TreadWheel induces changes in animal weight, again in a sex-and genotypedependent manner [32]. Thus, the Drosophila system is ideally suited to investigate the factors contributing to the variation in exercise response.…”

Exercise and the Brain: Lessons From Invertebrate Studies

“…In Lymnaea stagnalis , changes in biophysical properties of isolated serotonergic neurons were discovered, as well as the involvement of volume neurotransmission in adaptation of the nervous system to physical exercise (Dyakonova et al, 2019 ). In Drosophila spp., in well controlled experiments with different regimes of training, the responsive neuronal genes and metabolic pathways are identified (Watanabe and Riddle, 2021 ); the role of octopaminergic system is evidenced in genetic, pharmacological and behavioral studies (Sujkowski et al, 2017 , 2020 ; Cobb et al, 2020 ). In the cricket G. bimaculatus , the most complete repertoire of behavioral changes produced by flying have been described in neuroethological investigations on aggression (Hofmann and Stevenson, 2000 ), mating (Dyakonova and Krushinsky, 2008 ), auditory orientation (Sergejeva and Popov, 1994 ; Mezheritskiy et al, 2020 ).…”

“…This looks only as a temporal gap, as a number of neuronal genes and neuronal transcription regulators were reported recently to be affected by exercise in Drosophila spp. (Watanabe and Riddle, 2021 ).…”