Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis inCaenorhabditis elegans

Abstract

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...

Metabolic shift from glycogen to trehalose promotes lifespan and healthspan in Caenorhabditis elegans

“…To better understand the metabolic and phenotypic consequences of this change, we modeled a high-glucose diet in C. elegans. Addition of glucose to the media decreased lifespan similar to previous studies (5)(6)(7)(8)12), and higher concentrations of supplemental glucose resulted in correspondingly shorter lifespans ( Fig. 1A and SI Appendix, Table S1).…”

“…According to the US Department of Agriculture, the average individual consumed almost 100 pounds of sugar in 2015, more than double the amount consumed in 1900 (4). The effects of a high-sugar diet can be modeled in Caenorhabditis elegans, as the addition of glucose to the standard Escherichia coli diet has been shown to cause glucose toxicity, which results in a decrease in lifespan (5)(6)(7)(8), an increase in triglycerides (7,8), neuronal defects (9,10), and a decrease in locomotion (11,12). Intracellularly, excess glucose can also lead to a greater incidence of advanced glycation end products (AGEs) in both humans and C. elegans (13).…”

“…In addition to the glucose polymer glycogen, C. elegans can store sugar in the form of trehalose, a glucose disaccharide (26). Ad-dition of trehalose to the standard E. coli diet promotes longevity (27) in contrast to the toxicity caused by the addition of glucose (5)(6)(7)(8). Furthermore, mutants have been identified that are long lived and store increased trehalose (27).…”

The ETS-5 transcription factor regulates activity states in Caenorhabditis elegans by controlling satiety

“…High-glucose diets in humans are closely linked to obesity (43). Likewise, glucose supplementation to the C. elegans diet caused a significant rise in fat storage, likely by altering the quality of bacterial food grown on glucose (44) (Fig. S5 C and D).…”

Diet-responsive Transcriptional Regulation of Insulin in a Single Neuron Controls Systemic Metabolism

“…Worms fed OP50 grown on glucose have increased triacylglycerides, but carbohydrate levels are unaffected (Brooks et al, 2009). We, and others, have shown that feeding worms on OP50 + glucose drastically increases intestinal fat levels ( Figure 3F, (Garcia et al, 2015;Juozaityte et al, 2017)). We postulated that this increase in energy availability may elicit a response of the ETS-5/INS-1 regulatory module in the BAG neurons.…”