Diet is a central environmental factor that contributes to the phenotype and physiology of individuals. At the root of many human health issues is the excess of calorie intake relative to calorie expenditure. For example, the increasing amount of dietary sugars in the human diet is contributing to the rise of obesity and type 2 diabetes. Individuals with obesity and type 2 diabetes have compromised oxygen delivery, and thus it is of interest to investigate the impact a high-sugar diet has on oxygen deprivation responses. By utilizing the Caenorhabditis elegans genetic model system, which is anoxia tolerant, we determined that a glucose-supplemented diet negatively impacts responses to anoxia and that the insulin-like signaling pathway, through fatty acid and ceramide synthesis, modulates anoxia survival. Additionally, a glucose-supplemented diet alters lipid localization and initiates a positive chemotaxis response. Use of RNA-sequencing analysis to compare gene expression responses in animals fed either a standard or glucose-supplemented diet revealed that glucose impacts the expression of genes involved with multiple cellular processes including lipid and carbohydrate metabolism, stress responses, cell division, and extracellular functions. Several of the genes we identified show homology to human genes that are differentially regulated in response to obesity or type 2 diabetes, suggesting that there may be conserved gene expression responses between C. elegans fed a glucose-supplemented diet and a diabetic and/or obesity state observed in humans. These findings support the utility of the C. elegans model for understanding the molecular mechanisms regulating dietary-induced metabolic diseases.KEYWORDS sugar diet; oxygen deprivation; insulin signaling; gene expression; C. elegans T HE chronic and excessive intake of calories relative to daily energy expenditure often results in major heath issues such as obesity, metabolic syndrome, and type 2 diabetes (Ogden et al. 2012;Sonestedt et al. 2012). A recent change in the Western human diet, in comparison to traditional diets of the past, has been an increase in dietary saturated fats and sugars (e.g., sugar-sweetened beverage intake rose 135% between 1977 and 2001) (de Koning et al. 2011). Glucose, which is an essential component of metabolism and energy production, induces pancreatic b-cells to secrete insulin, which in turn facilitates the import of glucose into tissues such as muscle and adipose. However, a chronic overabundance of glucose and/or fructose will have deleterious effects on cellular and tissue functions. For example, an excess of dietary sugar leads to the inability of cells to respond correctly to insulin (insulin resistance), resulting in a decrease in glucose uptake by cells and an increase in glucose remaining within the circulatory system (hyperglycemia) (Brownlee 2001;Szablewski 2011). An excess of dietary sugars increases adipose tissue, triglycerides, and low-density lipoproteins (Szablewski 2011). An additional consequence of hype...

Cellular and genetic analysis supports the notion that NPP-16/NUP50 and CDK-1 function to reversibly arrest prophase blastomeres in Caenorhabditis elegans embryos exposed to anoxia. The anoxia-induced shift of cells from an actively dividing state to an arrested state reveals a previously uncharacterized prophase checkpoint in the C. elegans embryo.

Developing organisms require nutrients to support cell division vital for growth and development. An adaptation to stress, used by many organisms, is to reversibly enter an arrested state by reducing energy-requiring processes, such as development and cell division. This "wait it out" approach to survive stress until the environment is conductive for growth and development is used by many metazoans. Much is known about the molecular regulation of cell division, metazoan development and responses to environmental stress. However, how these biological processes intersect is less understood. Here, we review studies conducted in Caenorhabditis elegans that investigate how stresses such as oxygen deprivation (hypoxia and anoxia), exogenous chemicals or starvation affect cellular processes in the embryo, larvae or adult germline. Using C. elegans to identify how stress signals biological arrest can help in our understanding of evolutionary pressures as well as human health-related issues.

Individuals with type 2 diabetes display metabolic abnormalities, such as hyperglycemia, increased free fatty acids, insulin resistance, and altered ceramide levels, that contribute to vascular dysfunctions and compromised oxygen delivery. Caenorhabditis elegans fed a glucose-supplemented diet or with altered ceramide metabolism, due to a hyl-2 mutation, are sensitive to oxygen deprivation (anoxia). Our experiments showed that the combination of these factors further decreased the anoxia survival. RNA-sequencing analysis was performed to assess how a glucose-supplemented diet and/or a hyl-2 mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia-sensitive animals [hyl-2(tm2031) mutation or a glucose diet] revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens), or xenobiotic and endobiotic phase I and II detoxification system. Use of RNA interference (RNAi) to target gene products of the xenobiotic and endobiotic phase I and II detoxification system (UDP-glycosyltransferase and Cytochrome p450 genes; ugt-15, ugt-18, ugt-19, ugt-41, ugt-63, cyp-13A12, cyp-25A1, and cyp-33C8) increased anoxia survival in wild-type animals fed a standard diet. Anoxia sensitivity of the hyl-2(tm2031) animals was suppressed by RNAi of cyp-25A1 or cyp-33C8 genes. A glucose diet fed to the P0 hermaphrodite decreased the anoxia survival of its F1 embryos; however, the RNAi of ugt-63 and cyp-33C8 suppressed anoxia sensitivity. These studies provide evidence that the detoxification system impacts oxygen deprivation responses and that C. elegans can be used to model the conserved detoxification system.

Gamete cells pass on information to the next generation via DNA sequence and also through epigenetic mechanisms such as small RNAs, DNA methylation, or chromatin modifications. Caenorhabditis elegans is a genetic model system that an enormous number of talented researchers have used to understand biological phenomenon and develop molecular tools that have ultimately led to paradigm-shifting ideas in biology. Thus, this model is well poised to further investigate the molecular mechanisms involved with epigenetic modifications and transgenerational epigenetic inheritance. The strengths of this model system include a historical wealth of information regarding genetics, development, germline function, chromosome biology, and the regulation of gene expression. Using this system, one can investigate the mechanisms involved with how the germline passes on heritable epigenetic information to subsequent generations. Here, we highlight aspects about the biology of C. elegans that make it amenable to epigenetic studies, highlight some recent findings in the field of epigenetics, and comment on how this system would be beneficial for future biological studies involving epigenetic processes.