Biology subjects

Chaturbedi, A.

Publications and source records attributed to Chaturbedi, A..

3 recordsLinked to original sources

bioRxiv2023

Evolutionarily related host and microbial pathways regulate fat desaturation

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression1-4, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPAR in C. elegans. Untargeted metabolomics of a {beta}-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a {beta}- cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a {beta}-methyl fatty acid, bemeth#1, whose activity mimics that of microbiota-dependent becyp#1, but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated {beta}-oxidation pathway, while the endogenous bemeth#1 is metabolized via -oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPAR to regulate fat desaturation.

biochemistry↗

bioRxiv2023

Different gametogenesis states uniquely impact longevity in Caenorhabditis elegans.

Curtailed reproduction affects lifespan and fat metabolism in diverse organisms, suggesting a regulatory axis between these processes. In Caenorhabditis elegans, ablation of germline stem cells (GSCs) leads to extended lifespan and increased fat accumulation, suggesting GSCs emit signals that modulate systemic physiology. Previous studies mainly focused on the germline-less glp-1(e2141) mutant, however, the hermaphroditic germline of C. elegans provides an excellent opportunity to study the impact of different types of germline anomalies on longevity and fat metabolism. In this study, we compared the metabolomic, transcriptomic, and genetic pathway differences in three sterile mutants: germline-less glp-1, feminized fem-3, and masculinized mog-3. We found that although the three sterile mutants all accumulate excess fat and share expression changes in stress response and metabolism genes, the germline-less glp-1 mutant exhibits the most robust lifespan increase, whereas the feminized fem-3 mutant only lives longer at specific temperatures, and the masculinized mog-3 mutant lives drastically shorter. We demonstrated that overlapping but distinct genetic pathways are required for the longevity of the three different sterile mutants. Our data showed that disruptions of different germ cell populations result in unique and complex physiological and longevity consequences, highlighting exciting avenues for future investigations.

genetics↗

bioRxiv2022

Sex-specificity of the C. elegans metabolome

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and a series of germline mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provides a blueprint for the discovery of sex-dependent metabolites in other animals.

bioinformatics↗