Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.