The central nervous system is a major regulator of body fat. It is known that inappropriate integration of nutritional and satiety signals in the brain drives obesity and eating disorders. Therefore, identifying systemic mechanisms governed by the brain to control body fat would profoundly advance our understanding of such conditions. We use the nematode Caenorhabditis elegans to identify ancient mechanisms driving fat storage and food-seeking behaviour.
Animal behavior is shaped through interplay between genes, the environment and previous experience. As in other animals, nutritional status has a major influence on behaviour in C. elegans, where two principal nutritional states, hunger and satiety, generate opposite behaviours. Hungry animals actively seek food by roaming their environment; whereas, sated animals stop feeding and enter a motionless, quiescent state - similar to post-prandial sleep.
We have identified a conserved Ets-domain transcription factor ETS-5, orthologue of Pet1/FEV, that controls food-regulated behaviour. We found that loss of ETS-5 from four sensory neurons causes animals to abnormally enter quiescence. This behavioural defect is caused by the storage of excess intestinal fat. As neurons in C. elegans do not innervate the intestine, we hypothesized that ETS-5 transcriptionally controls a neuroendocrine factor(s) to control fat levels. By screening such factors, we identified a neuronal insulin that is regulated by ETS-5 and is required to control food-seeking behaviour. Remarkably, the mouse orthologue of ETS-5, Pet1, which is expressed in the brain and pancreas, also controls insulin expression in pancreatic b-cells. This suggests that in invertebrate species, neurons can perform endocrine functions of pancreatic cells in higher organisms. Therefore, our future studies to identify ETS-5 transcriptional targets and gene regulatory networks may provide novel insights into both pancreatic cell function and the enigmatic role of insulins and neuropeptides expressed in the brain.