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.DOI: http://dx.doi.org/10.7554/eLife.00429.001

TORC1 (target of rapamycin complex 1) plays a central role in regulating growth, development, and behavior in response to nutrient cues. We previously showed that leucine-derived monomethyl branched-chain fatty acids (mmBCFAs) and derived glucosylceramide promote intestinal TORC1 activity for post-embryonic development and foraging behavior in Caenorhabditis elegans. Here we show that clathrin/adaptor protein 1 (AP-1)-dependent intestinal apical membrane polarity and polarity-dependent localization of the vacuolar-type H + -ATPase (V-ATPase) mediate the impact of the lipid pathway on intestinal TORC1 activation. Moreover, NPRL-3 represses mmBCFA-dependent intestinal TORC1 activity at least partly by regulating apical membrane polarity. Our results provide new insights into TORC1 regulation by lipids and membrane polarity in a specific tissue.Supplemental material is available for this article.Received April 8, 2015; revised version accepted May 29, 2015. Regulatory mechanisms that coordinate nutrient availability and metabolic status with growth, development, and behaviors are critical for animals' survival. The TORC1 (target of rapamycin complex 1) pathway is one of the major signaling pathways known to sense the levels of nutrients and metabolites-including amino acids, growth factors, and energy-for a broad range of physiological functions (Zoncu et al. 2011). Many studies indicate that TORC1 is activated by multiple mechanisms to account for variations in upstream signals. For example, the TSC/Rheb and AMPK pathways mediate the growth factor (insulin) and energy level-dependent TORC1 activity, respectively (Laplante and Sabatini 2012;Jewell et al. 2013). Mechanisms of TORC1 activation by certain nutrients such as amino acids and lipids are less clear and appear to be independent of these known signaling pathways (Laplante and Sabatini 2012;Jewell et al. 2013;Zhu et al. 2013). Recent studies have also indicated that different mechanisms are involved in TORC1 activation by different amino acids (Jewell et al. 2015;Wang et al. 2015). Therefore, despite extensive studies in the TORC1 field, outstanding questions regarding cellular and molecular mechanisms underlying TORC1 activation remain to be answered. In addition, studies using animal models are needed to analyze TORC1 regulation and functions in specific tissues for specific physiological functions.Caenorhabditis elegans is an excellent model to study TOR signaling-related physiological functions, including development, aging, metabolism and, behaviors (Vellai et al. 2003;Sheaffer et al. 2008;Jones et al. 2009;Soukas et al. 2009;Robida-Stubbs et al. 2012;Webster et al. 2013). We previously established a regulatory connection between a lipid biosynthesis pathway and TORC1 activation in the C. elegans intestine. We showed that monomethyl branched-chain fatty acids (mmBCFAs) and their derived sphingolipid glucosylceramide (GlcCer) impact post-embryonic growth, development, and foraging behavior (Kniazeva et al. 2008(Kniazeva et al. , 2015Zhu et al. 2013). T...

Food deprivation suppresses animal growth and development but spares the systems essential for foraging. The mechanisms underlying this selective development, and potential roles of lipids in it, are unclear. When C. elegans hatch in a food-free environment, postembryonic growth and development stall, but sensory neuron differentiation and neuronal development required for food responses continue. Here, we show that monomethyl branched-chain fatty acids (mmBCFAs) and their derivative, d17iso-glucosylceramide, function in the intestine to promote foraging behavior and sensory neuron maturation through both TORC1-dependent and -independent mechanisms. We show that mmBCFAs impact the expression of a subset of genes, including ceh-36/Hox, which we show to play a key role in mediating the regulation of the neuronal functions by this lipid pathway. This study uncovers that a lipid pathway promotes neuronal functions involved in foraging under both fed and fasting conditions and adds critical insight into the physiological functions of TORC1.