Abstract/Summary

Maternal obesity impacts both the current generation and the offspring of obese mothers, including a greater risk of developing the metabolic syndrome and increased adiposity in later life. However, the extent of the impact of maternal obesity on offspring and the mechanisms involved remain unclear. Here the nematode, Caenorhabditis elegans, is established as a tractable model for studying maternal obesity. This glucose induced maternal obesity model is utilised to assess the long-term and multigenerational impacts of an obesogenic diet on lifespan, fitness and healthspan. The triglyceride content of offspring from glucose fed mothers is increased, regardless of which generation of worms have been exposed to glucose. This suggests that maternal glucose exposure results in offspring with altered metabolic pathways and susceptibility to increased lipid accumulation irrespective of the offspring’s diet. Direct glucose exposure resulted in reduced lifespan, motility, fertility, dopaminergic function and mitochondrial function. Control fed offspring whose mothers were exposed to glucose had reduced lifespan (0.2% glucose) and fertility (2% glucose), with aged nematodes displaying decreased dopaminergic function and survival following thermal stress, suggesting that some detrimental outcomes of a glucose diet can be inherited. The epigenetic regulators MYS-1/KAT5, MYS-2/KAT8, PHF-15/JADE3, SPR-5/LSD1A, MET-2/SETDB1 and WDR-5.1/WDR5 are required for the transgenerational inheritance of a high lipid phenotype. Furthermore, the insulin/insulin-like growth factor signalling pathway transcription factor, DAF-16/FOXO, and nuclear hormone receptors, NHR-14/HNF4 and SEX-1/PPAR, are important regulators of transgenerational obesity in this nematode model. Direct exposure to the gestational diabetes drug, metformin, could reduce adiposity in the treated generation. Preliminary data shows that the deletion of orthologs of selected human high BMI-associated risk genes, identified in genome-wide association studies, are associated with increased lipid content. This nematode model of maternal obesity offers a high throughput and cheap platform for identifying genetic and environmental factors co-regulating obesity and associated metabolic dysfunction. Further research into the mechanisms involved and potential therapeutics and are needed to fully elucidate the effects of maternal obesity on subsequent generations.