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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, 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 inC. 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 activatesfat-7expression 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, which mimics the activity 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 offat-7expression 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.
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This content will become publicly available on October 21, 2026
Nuclear receptor-neurotransmitter coupling links behavior to metabolic state
Summary Animals must flexibly respond to environmental stimuli to survive, and optimal responses critically depend on the organism’s current needs. Many organisms have evolved both cell-intrinsic and intertissue signaling pathways that integrate metabolic status. However, how this information is encoded in molecular signals is currently not well understood. Here we show that the nematodeC. elegansemploys lipidated neurohormones that combine the neurotransmitter octopamine and fat metabolism-derived building blocks to relay information about lipid metabolic status and drive inhibition of aversive olfactory responses during food removal. Using targeted metabolomics, we show that lipidated neurohormone synthesis requires the carboxylesterase CEST-2.1, which links octopamine-glucosides with endogenous methyl-branched or diet-derived cyclopropane fatty acids that act as agonists of the nuclear receptor and master regulator of fat metabolism, NHR-49/PPARα. Loss ofcest-2.1,loss of bacterial cyclopropane fatty acid production, or loss of endogenous biosynthesis of the methyl-branched fatty acid substrates of CEST-2.1 mimics the behavioral responses of animals lacking octopamine, indicating that regulation of neurotransmitter-dependent behavior is linked to the coordination of fat metabolism via NHR-49/PPARα. Biosynthesis and subsequent neuromodulation via lipidated neurohormone relies on an intertissue trafficking pathway in which octopamine is shuttled first into the intestine where it is chemically modified, which is likely followed by neuronal import and intracellular hydrolysis to finally release free octopamine. We propose that esterase-dependent synthesis and subsequent hydrolysis of lipidated neurohormones represents a chemical encoding mechanism by which animals integrate information from neurotransmitter signaling and lipid homeostasis to direct appropriate behaviors.
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- Award ID(s):
- 2042101
- PAR ID:
- 10647383
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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