A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk

The mTOR-dependent nutrient-sensing and response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient and metabolite signals up-stream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially at the organism level. We previously showed glucosylceramide (GlcCer) acts as a critical nutrient and metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. Here, through a large-scale genetic screen, we find that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, GlcCer deficiency, inactive mTORC1, or prolonged starvation relocates intestinal peroxisomes closer to the apical region in a kinesin-and microtubule-dependent manner. Those apical accumulated peroxisomes further release peroxisomal-b-oxidation-derived glycolipid hormones that target chemosensory neurons and downstream nuclear hor-mone receptor DAF-12 to arrest the animal development. Our data illustrate a sophisticated gut-brain axis that predominantly orchestrates nutrient-sensing-dependent development in animals.

Automated summary

The mTOR-dependent nutrient-sensing and response machinery is essential for animals to regulate cellular and developmental programs. However, the specific nutrient and metabolite signals involved in mTOR regulation and their effects at the organism level are not well understood. In this study, the researchers identified the critical role of intestinal peroxisomes in antagonizing the GlcCer-mTORC1-mediated nutrient signal. They found that GlcCer deficiency, inactive mTORC1, or prolonged starvation caused the relocation of intestinal peroxisomes closer to the apical region, leading to the release of glycolipid hormones that affect animal development. These findings highlight the importance of the gut-brain axis in nutrient-sensing-dependent development in animals.