RESUMEN
Obesity has dramatically increased in prevalence, making it essential to understand its accompanying metabolic changes. Modeling diet-induced obesity in Drosophila melanogaster (fruit flies), we elucidated transcriptional and metabolic changes in w (1118) flies on a high-fat diet (HFD). Mass spectrometry-based metabolomics revealed altered fatty acid, amino acid, and carbohydrate metabolism with HFD. Microarray analysis uncovered transcriptional changes in nitrogen metabolism, including CG9510, homolog of human argininosuccinate lyase (ASL). CG9510 knockdown in flies phenocopied traits observed with HFD, namely increased triglyceride levels and decreased cold tolerance. Restoration of CG9510 expression ameliorated observed negative consequences of HFD. Metabolomic analysis of CG9510 knockdown flies confirmed functional similarity to ASL, regulating the balance of carbon and nitrogen metabolism. In summary, we found that HFD suppresses CG9510 expression, a gene required for proper triglyceride storage and stress tolerance. These results draw an important link between regulation of amino acid metabolism and the response to diet-induced obesity.
RESUMEN
Obesity is associated with many diseases, one of the most common being obstructive sleep apnea (OSA), which in turn leads to blood gas disturbances, including intermittent hypoxia (IH). Obesity, OSA and IH are associated with metabolic changes, and while much mammalian work has been done, mechanisms underlying the response to IH, the role of obesity and the interaction of obesity and hypoxia remain unknown. As a model organism, Drosophila offers tremendous power to study a specific phenotype and, at a subsequent stage, to uncover and study fundamental mechanisms, given the conservation of molecular pathways. Herein, we characterize the phenotype of Drosophila on a high-fat diet in normoxia, IH and constant hypoxia (CH) using triglyceride and glucose levels, response to stress and lifespan. We found that female flies on a high-fat diet show increased triglyceride levels (p<0.001) and a shortened lifespan in normoxia, IH and CH. Furthermore, flies on a high-fat diet in normoxia and CH show diminished tolerance to stress, with decreased survival after exposure to extreme cold or anoxia (p<0.001). Of interest, IH seems to rescue this decreased cold tolerance, as flies on a high-fat diet almost completely recovered from cold stress following IH. We conclude that the cross talk between hypoxia and a high-fat diet can be either deleterious or compensatory, depending on the nature of the hypoxic treatment.