Energy homeostasis occupies a central position in biology, as it regulates gene expression, signal transduction, cellular survival, fertility, and lifespan. However, the molecular and genetic responses to excess nutrients are poorly understood. Using C. elegans as a genetic model to study the pathways that respond to nutrient stress, we have identified roles for O-GlcNAc cycling and insulin signaling in the glucose stress response. O-GlcNAc (O-linked-N-acetyl glucosamine) is a post-translational modification catalyzed by the O-GlcNAc transferase OGT-1 and the O-GlcNAcase OGA-1. Glucose levels influence O-GlcNAc modification levels, suggesting that the pathway acts as a nutrient sensor. Over 500 nuclear and cytoplasmic proteins are O-GlcNAc modified, including components of the insulin-signaling pathway. In addition, OGA-1 is a human type II diabetes susceptibility locus. Although these enzymes are essential in mammals and highly conserved in C. elegans, knockouts of
oga-1 and
ogt-1 are viable in the worm. Our previous work demonstrated that O-GlcNAc cycling regulates insulin signaling in the insulin-like receptor mutant
daf-2. Null mutations in
ogt-1 selectively enhance
daf-2 insulin signaling, leading to decreased dauer formation and lifespan with no effect on fertility. Conversely,
oga-1 mutations extend
daf-2 lifespan, and this effect is partially dependent on the DAF-16 transcription factor. We tested whether the O-GlcNAc cycling or insulin signaling pathways were involved in the genetic response to nutrient stress. We find that
ogt-1 mutants show decreased fertility on high glucose. We also found that excess glucose is an enhancer of insulin signaling, suppressing
daf-2 dauer formation. Furthermore, combining glucose stress with decreased insulin signaling in a
daf-2 ogt-1 double mutant results in increased carbohydrate storage, decreased fertility, and a partial restoration of dauer formation. These data suggest that O-GlcNAc cycling and its regulation of the insulin-singaling pathway are necessary for the maintenance of energy homeostasis in response to glucose stress. We are currently screening a C. elegans RNAi library to identify additional factors that, like
ogt-1, suppress insulin signaling in the presence of glucose stress. This screen will identify additional pathways that respond to nutrient stress and will provide insight into how cells respond to nutrient stress when insulin signaling is compromised.