EAT-2 attenuates C. elegans development via metabolic remodeling in a chemically defined food environment

by Selleckchem | Nov 06 2023

Dietary intake and nutrient composition regulate animal growth and development; however, the underlying mechanisms remain elusive. Our previous study has shown that either the mammalian deafness homolog gene tmc-1 or its downstream acetylcholine receptor gene eat-2 attenuates Caenorhabditis elegans development in a chemically defined food CeMM (C. elegans maintenance medium) environment, but the underpinning mechanisms are not well-understood. Here, we found that, in CeMM food environment, for both eat-2 and tmc-1 fast-growing mutants, several fatty acid synthesis and elongation genes were highly expressed, while many fatty acid β-oxidation genes were repressed. Accordingly, dietary supplementation of individual fatty acids, such as monomethyl branch chain fatty acid C17ISO, palmitic acid and stearic acid significantly promoted wild-type animal development on CeMM, and mutations in either C17ISO synthesis gene elo-5 or elo-6 slowed the rapid growth of eat-2 mutant. Tissue-specific rescue experiments showed that elo-6 promoted animal development mainly in the intestine. Furthermore, transcriptome and metabolome analyses revealed that elo-6/C17ISO regulation of C. elegans development may be correlated with up-regulating expression of cuticle synthetic and hedgehog signaling genes, as well as promoting biosynthesis of amino acids, amino acid derivatives and vitamins. Correspondingly, we found that amino acid derivative S-adenosylmethionine and its upstream metabolite methionine sulfoxide significantly promoted C. elegans development on CeMM. This study demonstrated that C17ISO, palmitic acid, stearic acid, S-adenosylmethionine and methionine sulfoxide inhibited or bypassed the TMC-1 and EAT-2-mediated attenuation of development via metabolic remodeling, and allowed the animals to adapt to the new nutritional niche.

Comments:

The passage you provided describes a study conducted on the nematode Caenorhabditis elegans to investigate the mechanisms by which dietary intake and nutrient composition influence animal growth and development. The study focused on two genes, tmc-1 and eat-2, and their effects on C. elegans development in a chemically defined food environment called CeMM (C. elegans maintenance medium). The researchers found that mutations in either the tmc-1 or eat-2 genes led to attenuated development in CeMM.

Further investigation revealed that in CeMM, both the eat-2 and tmc-1 mutants exhibited increased expression of genes involved in fatty acid synthesis and elongation, while genes associated with fatty acid β-oxidation were suppressed. This suggests that altered fatty acid metabolism may play a role in the development of these mutants. To explore this further, the researchers supplemented the CeMM diet with specific fatty acids, such as C17ISO, palmitic acid, and stearic acid, and observed that these supplements significantly promoted wild-type animal development on CeMM. Additionally, mutations in genes involved in C17ISO synthesis, specifically elo-5 or elo-6, were found to slow down the rapid growth of the eat-2 mutant. Tissue-specific rescue experiments demonstrated that elo-6 primarily promoted animal development in the intestine.

Further analyses of the nematodes' transcriptome and metabolome indicated that elo-6 and C17ISO regulation of C. elegans development might be linked to increased expression of genes involved in cuticle synthesis and hedgehog signaling, as well as enhanced biosynthesis of amino acids, amino acid derivatives, and vitamins. In line with these findings, the researchers discovered that the amino acid derivative S-adenosylmethionine and its upstream metabolite methionine sulfoxide significantly promoted C. elegans development on CeMM. This suggests that these metabolites could overcome or bypass the developmental attenuation caused by TMC-1 and EAT-2 via metabolic remodeling, enabling the animals to adapt to the new nutritional environment.

In summary, this study provides insights into the mechanisms underlying the regulation of C. elegans development by dietary factors. The specific fatty acids C17ISO, palmitic acid, and stearic acid, as well as the metabolites S-adenosylmethionine and methionine sulfoxide, were found to counteract the developmental effects of tmc-1 and eat-2 mutations through metabolic remodeling. These findings contribute to our understanding of how dietary intake and nutrient composition influence animal growth and development at a molecular level.