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

Abstract

To maintain metabolic homeostasis, the nervous system must adapt and respond to an ever-changing environment. Transcription factors are key drivers of this adaptation, eliciting gene expression changes that can alter neuronal activity. Here we show in Caenorhabditis elegans that the terminal selector transcription factor ETS-5 not only establishes the identity of the BAG sensory neurons, but is re-purposed to shape the functional output of the BAG neurons post-mitotically. We find that ETS-5 directly regulates the expression of INS-1, an insulin-like peptide, in the BAG sensory neurons. INS-1 expression in the BAG neurons, and not in other INS-1-expressing neurons, decreases intestinal lipid levels and promotes foraging behaviour. Using in vivo analysis, we show that elevated intestinal lipid stores, driven by a high glucose diet, downregulates ETS-5-driven expression of INS-1. Together, our data reveal an inter-tissue regulatory loop by which a single neuron can control systemic metabolism, and that the activity of this neuron is modulated by the metabolic state of the organism.