A lipid-mTORC1 nutrient sensing pathway regulates animal development by peroxisome-derived hormones

Abstract

Animals have developed many signaling mechanisms that alter cellular and developmental programs in response to changes in nutrients and their derived metabolites, many of which remain to be understood. We recently uncovered that glucosylceramides, a core sphingolipid, act as a critical nutrient signal for overall amino-acid level to promote development by activating the intestinal mTORC1 pathway. However, how the intestinal GlcCer-mTORC1 activity regulates development throughout the whole body is unknown. Through a large-scale genetic screen, we found that the peroxisomes are critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, deficiency of glucosylceramide, inactivation of the downstream mTORC1 activity, or prolonged starvation relocated peroxisomes closer to the intestinal apical region to release peroxisomal-beta-oxidation derived hormones that targeting chemosensory neurons to arrest the animal development. Our data illustrated a new gut-brain axis for orchestrating nutrient-sensing dependent development in Caenorhabditis elegans, which may also explain why glucosylceramide and peroxisome become essential in metazoans.

Free long chain fatty acid solitarily primes early postembryonic development inCaenorhabditis elegansunder starvation

“…Furthermore, blocking peroxisome function by mutation of prx-11/PEX11 , which important for peroxisome proliferation(Li et al, 2021; Thieringer et al, 2003), also inhibited the FEDUS (Fig. 4G,H), even though prx-11 was not essential for L1 development (Li et al, 2021; Thieringer et al, 2003; Wang et al, 2013). These data suggested that NHR-49/80 dependent peroxisome activation plays a critical role in FEDUS.…”

“…2B, C). We then measured the mTORC1 activity by the relative intestinal nucleolar size labeled by the FIB-1 antibody (because mammalian phosphorylated-S6K antibodies could not recognize its C. elegans ortholog RSKS-1) (Li et al, 2021; Ma et al, 2016; Sheaffer et al, 2008; Zhu et al, 2021a). Interestingly, we found the mTORC1 activity was further reduced, rather than increased under the palmitate supplementation (Fig.…”

“…PPARα/NHR-49 could activate the biosynthesis of multiple metabolites in peroxisomes, such as metabolites from the sterol de novo pathway, peroxisomal beta-oxidation or alkyl-glycerophospholipids. These metabolites could function as signals to mediate the FEDUS (Islinger et al, 2018; Li et al, 2021; Ludewig and Schroeder, 2013; Watterson et al, 2022; Xu et al, 2011). We first excluded metabolites in the de novo sterols pathway, because (1) supplement of several important intermediate metabolites in this pathway, such as mevalonate or coenzyme Q9 could not initiate the development under fasting (Fig.…”

“…The critical role of peroxisome in FEDUS is very intriguing, especially because we recently have identified that C. elegans negatively regulated its L1 development via repositioning of peroxisomes to the apical region of intestine (e.g., close to the intestinal lumen) by Kinesin and facilitating a family of peroxisome-derived secretive metabolite hormones (Li et al, 2021). We then tested whether the FEDUS could also be regulated in a similar way.…”

“…These metabolites could function as signals to mediate the FEDUS (Islinger et al, 2018;Li et al, 2021;Ludewig and Schroeder, 2013;Watterson et al, 2022;Xu et al, 2011). We first excluded metabolites in the de novo sterols pathway, because (1) supplement of several important intermediate metabolites in this pathway, such as mevalonate or coenzyme Q9 could not initiate the development under fasting (Fig.…”