A Sphingolipid-mTORC1 Nutrient-Sensing Machinery Enables Animal Development by Suppression of the Intestinal Peroxisome Relocation, Hormone Secretion and the Gut-Brain Crosstalk

The mTOR dependent nutrient-sensing/response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient/metabolite signals upstream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially in the organism level. We recently uncovered glucosylceramide, the core structure of glucosylated sphingolipids, acts as a critical nutrient/metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. In this work, through a large-scale genetic screen, we found that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, deficiency of glucosylceramide, inactivation of mTORC1 activity, or prolonged starvation relocated intestinal peroxisomes closer to the apical region in a kinesin/microtubule-dependent manner. Those apical accumulated peroxisomes further released peroxisomal-beta-oxidation-derived glycolipid hormones that targeting chemosensory neurons and downstream nuclear hormone receptor DAF-12 to arrest the animal development. Our data illustrated a new gut-brain axis that predominantly orchestrates the nutrient-sensing-dependent development in vivo, which may also explain why glucosylceramide and peroxisome become essential in animal development.