Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila

Abstract

20Obesity and its co-morbidities are a growing health epidemic. Interactions between 21 genetic background and the environment and behavior (i.e. diet) greatly influence 22 organismal energy balance. Previously, we described obesogenic mutations in the 23 gene Split ends (Spen) in Drosophila melanogaster, and roles for Spen in fat storage 24 and metabolic state. In Spen-deficient storage cells lipid catabolism is impaired, 25 accompanied by a compensatory increase in glycolytic flux and protein catabolism. 26Here we investigate gene-diet interactions to determine if diets supplemented with 27 specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We 28show that a high-yeast diet partially rescues adiposity and developmental defects. High 29 sugar partially improves developmental timing as well as adult longevity. Gene-diet 30 interactions were heavily influenced by developmental-stage-specific organismal needs: 31 extra yeast provides benefits early in development (larval stages) but becomes 32 detrimental in adulthood. High sugar confers benefits at both larval and adult stages, 33 with the caveat of increased adiposity. A high-fat diet is detrimental according to all 34 tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic 35 responses to supplemented diets, diet was the dominant factor in directing the whole-36 organism steady-state metabolome. Obesity is a complex disease of genetic, 37 environmental, and behavioral inputs. Our results show that diet customization can 38 ameloriate metabolic dysfunction underpinned by a genetic factor. 39 utilization of nutrients (catabolism) to nutrient storage (anabolism). 50While diet can be a major driver of fat storage, gene-environment interactions 51 play a critical yet poorly understood role in the development of obesity and metabolic 52 syndrome, defined as "clustering of abdominal obesity, dyslipidemia, hyperglycemia and 53 hypertension" (Giovannucci 2007). Decades ago, the increased incidence of Diabetes 54Mellitus was attributed to an evolutionarily beneficial 'thrifty' genotype that is 55 incompatible with the modern Western Diet and lifestyle (Neel 1962). Evidence of 56 genetic adaptation to a diet high in polyunsaturated fatty acids can be found in the 57 genomes of Greenlandic Inuit, in the form of genetic variants in fatty acid desaturases 58 (Fumagalli et al. 2015;Chen et al. 2019). Accordingly, developing a comprehensive 59 understanding of obesity and metabolic syndrome demands examination of the interplay 60 between genetics and diet. 61Drosophila melanogaster is an excellent model in which to study gene function in 62 metabolism (Grönke et al. 2003(Grönke et al. , 2005Baker and Thummel 2007; Leopold and 63 Perrimon 2007;Schlegel and Stainier 2007;Guo et al. 2008;Beller et al. 2010; Reis et 64 al. 2010;Hazegh et al. 2017;Musselman and Kuhnlein 2018). Metabolic pathways are 65 highly conserved in Drosophila (Bernards and Hariharan 2001) and many fat regulatory 66 genes have functional orthol...