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Evolutionarily related host and microbial pathways regulate fat desaturation.

ABSTRACT: 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 expression^1-4, 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/PPARα in C. elegans. Untargeted metabolomics of a β-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a β-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 β-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 β-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.

SUBMITTER: Fox BW

PROVIDER: S-EPMC10491262 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Evolutionarily related host and microbial pathways regulate fat desaturation.

Fox Bennett W BW Helf Maximilian J MJ Burkhardt Russell N RN Artyukhin Alexander B AB Curtis Brian J BJ Palomino Diana Fajardo DF Chaturbedi Amaresh A Tauffenberger Arnaud A Wrobel Chester J J CJJ Zhang Ying K YK Lee Siu Sylvia SS Schroeder Frank C FC

bioRxiv : the preprint server for biology 20230831

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 expression<sup>1-4</sup>, 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/PPARα in <i>C. elegans</i>. Untargeted metabolomics of a ...[more]

PMID: 37693574

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Project description:Diet-induced obesity (DIO) is rapidly becoming a global health problem, particularly as Westernization of emerging nations continues. Currently, one third of adult Americans are considered obese and, if current trends continue, >90% of US citizens are predicted to be affected by 2050. However, efforts to fight this epidemic have not yet produced sound solutions for prevention or treatment. Our studies reveal a balanced and chronobiological relationship between food consumption, daily variation in gut microbial evenness and function, basomedial hypothalamic circadian clock (CC) gene expression, and key hepatic metabolic regulatory networks , including CC and nuclear receptors (NR), that is are essential for metabolic homeostasis. “Western” diets high in saturated fats dramatically alter diurnal variation in microbial composition and function, which in turn lead to uncoupling of the hepatic CC and NR networks from central CC control in ways that offset the timing and types of regulatory factors directing metabolic function. These signals include microbial metabolites such as short chain fatty acids (SCFAs) and hydrogen sulfide (H2S) that can directly regulate or disrupt metabolic networks of the hepatocyte. Our study therefore provides insights into the complex and dynamic relationships between diet, gut microbes, and the host that are critical for maintenance of health. Perturbations of this constellation of processes, in this case by diet-induced dysbiosis and its metabolomic signaling, can potentially promote metabolic imbalances and disease. This knowledge opens up many possibilities for novel therapeutic and interventional strategies to treat and prevent DIO, ranging from the manipulation of gut microbial function to pharmacological targeting of host pathways to restore metabolic balance. Mice were raised under germ-free or specific pathogen-free condition, or germ-free followed by conventionization. Liver tissues were harvested for total RNA isolation and hybridization on Affymetrix microarrays

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Evolutionarily related host and microbial pathways regulate fat desaturation.

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Evolutionarily related host and microbial pathways regulate fat desaturation.

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