Diet represents an exogenous influence that often yields colossal effects on an individual's phenotype, physiology and long-term health. The overconsumption of dietary sugars for example, has contributed to significant increases in obesity and type-2 diabetes; health issues that are costly both economically and in terms of human life. Individuals who are obese or are type 2 diabetic often have compromised oxygen delivery and an increased vulnerability to oxygen-deprivation related complications, such as ischemic stroke, macrovascular disease and myocardial infarction. Thus, it is of interest to identify the molecular changes glucose supplementation or hyperglycemia can induce, which ultimately compromise oxygen deprivation responses. C. elegans is anoxia tolerant unless fed a glucose-supplemented diet. Glucose-supplementation also alters lipid accumulation and increases sensitivity to paraquat-induced oxidative stress, suggesting that glucose is an obesity mimetic and compromises stress resistance. We determined that daf-2(e1370) animals are resistant to glucose-induced anoxia sensitivity, and this resistance is dependent upon activity of transcription factor DAF-16. The daf-2(e1370) resistance is modulated via multiple pathways including fatty acid (fat genes) and ceramide biosynthesis (hyl-2) as well as antioxidant activity (sod-2;sod-3). We hypothesize that a central aspect of glucose-induced anoxia sensitivity is mitochondrial dysfunction via disruption of lipid and ceramide homeostasis and changes in reactive oxygen species. To further test this hypothesis and determine how glucose supplementation impacts C. elegans we used RNA-sequencing to compare the gene expression profiles of animals fed either a standard or a glucose-supplemented diet. Glucose supplementation significantly impacts the expression of genes involved with multiple cellular processes including lipid and carbohydrate metabolism, stress responses, cell division and extracellular functions. We are using RNAi to identify gene expression changes that have a role in glucose-induced anoxia sensitivity. Furthermore, several of the genes differentially regulated in glucose supplemented C. elegans are also differentially regulated in humans with obesity or type-2 diabetes, indicating a degree of conserved gene expression changes between glucose-supplemented C. elegans and those observed in diabetic and/or obese human individuals. Together these data demonstrate that C. elegans can be used to further elucidate the molecular mechanisms regulating dietary-induced metabolic diseases and their associated complications.

Affiliation:
- Department of Biological Sciences, University of North Texas, Denton, TX