Intestinal peroxisomal fatty acid β-oxidation regulates neural serotonin signaling through a feedback mechanism

• Published in: PLoS biology Vol. 17; no. 12; p. e3000242
• Main Authors: Bouagnon, Aude D, Lin, Lin, Srivastava, Shubhi, Liu, Chung-Chih, Panda, Oishika, Schroeder, Frank C, Srinivasan, Supriya, Ashrafi, Kaveh
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2019; Public Library of Science (PLoS)
• Subjects: Acyl Coenzyme A - metabolism; Animals; Behavior; Biology and Life Sciences; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - metabolism; Circuits; Egg laying; Energy balance; Fasting; Fatty acids; Fatty Acids - metabolism; Feedback; Feeding; Feeding behavior; Feeding Behavior - physiology; Food; Homeostasis; Information processing; Intestine; Intestines - physiology; Kinases; Medicine and Health Sciences; Metabolic response; Metabolism; Metabolites; Metabolomics; Neurons; Neurons - metabolism; Neurosciences; Oxidation; Oxidation-Reduction; Peroxisomes - metabolism; Phospholipids; Physical Sciences; Physiology; Potassium; Research and Analysis Methods; Satiety; Serotonin; Serotonin - metabolism; Signal Transduction; Signaling; Transcription; New York; La Jolla California; San Francisco California; California; United States > US
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000242

The ability to coordinate behavioral responses with metabolic status is fundamental to the maintenance of energy homeostasis. In numerous species including Caenorhabditis elegans and mammals, neural serotonin signaling regulates a range of food-related behaviors. However, the mechanisms that integrate metabolic information with serotonergic circuits are poorly characterized. Here, we identify metabolic, molecular, and cellular components of a circuit that links peripheral metabolic state to serotonin-regulated behaviors in C. elegans. We find that blocking the entry of fatty acyl coenzyme As (CoAs) into peroxisomal β-oxidation in the intestine blunts the effects of neural serotonin signaling on feeding and egg-laying behaviors. Comparative genomics and metabolomics revealed that interfering with intestinal peroxisomal β-oxidation results in a modest global transcriptional change but significant changes to the metabolome, including a large number of changes in ascaroside and phospholipid species, some of which affect feeding behavior. We also identify body cavity neurons and an ether-a-go-go (EAG)-related potassium channel that functions in these neurons as key cellular components of the circuitry linking peripheral metabolic signals to regulation of neural serotonin signaling. These data raise the possibility that the effects of serotonin on satiety may have their origins in feedback, homeostatic metabolic responses from the periphery.