Regulation of animal development in response to nutritional cues is an intensely studied problem related to disease and aging. While extensive studies indicated roles of the Target of Rapamycin (TOR) in sensing certain nutrients for controlling growth and metabolism, the roles of fatty acids and lipids in TOR-involved nutrient/food responses are obscure. Caenorhabditis elegans halts postembryonic growth and development shortly after hatching in response to monomethyl branched-chain fatty acid (mmBCFA) deficiency. Here, we report that an mmBCFA-derived sphingolipid, d17iso-glucosylceramide, is a critical metabolite in regulating growth and development. Further analysis indicated that this lipid function is mediated by TORC1 and antagonized by the NPRL-2/3 complex in the intestine. Strikingly, the essential lipid function is bypassed by activating TORC1 or inhibiting NPRL-2/3. Our findings uncover a novel lipid-TORC1 signaling pathway that coordinates nutrient and metabolic status with growth and development, advancing our understanding of the physiological roles of mmBCFAs, ceramides, and TOR.
Animals require nutrients, including carbohydrates, lipids, and amino acids, for development and growth, and to maintain the normal functioning of cells. However, in most natural environments, the availability of food tends to fluctuate. Some animals have therefore acquired the ability to dramatically reduce their metabolic activity, and thus their energy and nutrient needs to survive fasting conditions.
Caenorhabditis elegans is a transparent nematode worm that is used extensively as a model organism. When C. elegans larvae hatch in a food-free environment, they enter a quiescent state in which they suspend growth and cell division to conserve energy. However, the mechanisms that underlie this ability are not fully understood.
Here, Zhu et al. reveal that a type of lipid called a sphingolipid is required for C. elegans larvae to begin postembryonic development. When this lipid is absent in the environment and not synthesized internally, the larvae remain in a state of arrested development, which can be overcome by resupplying the lipid. Zhu et al. show that the lipid acts through a signaling pathway involving an enzyme complex called TORC1 and that the effect of the lipid can be blocked by another protein complex called NPRL-2/3. TORC1 is well known for its role in sensing amino acids and growth factors, but this is the first time that it has been shown to be involved in detecting lipids. Strikingly, Zhu et al. also show that, in the absence of the lipid, postembryonic growth and development can be initiated by activating TORC1 or inhibiting NPRL-2/3.
The work of Zhu et al. thus reveals a novel regulatory function of a specific fatty acid and sphingolipid variant that is used by C. elegans to coordinate its growth and development with its metabolic status or the availability of nutrients. Since all components of the pathway are conserved in mammals, the results could help to improve our understanding of how caloric restriction influences human health and aging.