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

It is lunch time and, involuntarily, you start feeling hungry and initiate the search for food. The opposite happens after a meal, when you feel satiated and do not feel the need for seeking food. This appetite control mechanism is common in the animal kingdom and is regulated by neural pathways that adjust metabolic status to energy intake. Different sensors “speak” to the central nervous system about nutrient abundance in the organism, which initiate or repress signals that lead to food intake. These pathways of appetite control are impaired in obesity and related diseases, but despite the high prevalence of these diseases, the molecular basis of feeding circuits is not completely understood.

One of the main pathways that regulates feeding is serotonergic signaling, which also regulates fat metabolism. Fats constitute one of the main energy storage for animals, but their use needs to be tightly controlled in order to sustain homeostasis. Under nutrient scarcity, feeding behaviour is promoted, and fats are mobilized from internal stores as free fatty acids, activated to acyl-CoA molecules, and transported to mitochondria and peroxisomes for obtaining ATP by beta-oxidation. This metabolic process consumes large amounts of oxygen, so oxygen availability has to be monitored to allow fats to be mobilized. As beautifully exemplified by Niels Ringstad (Ringstad 2016), think of a gasoline engine that delivers fuel and oxygen to a piston in order to generate force. When the ratio of fuel (representing fat) to oxygen changes, the efficiency of the engine is affected. This is solved by engineers with oxygen and fuel sensors that allow to adjust the mix. Nature has its own sensor system to fine tune behavioural responses with metabolic status and environmental stimuli. However, there are still many questions about how such integration mechanistically happens. One good model to study this neurometabolic pathway is the nematode C. elegans, in which oxygen-sensing neurons were discovered. These neurons, called URX neurons, couple oxygen-sensing to the metabolic use of fat stores (Witham et al. 2016). However, the metabolic pathways and the nutrient cues involved in this metabolic sensor remain largely undefined.

 

Results

Bouagnon et al. identified in this preprint the components of a circuit that integrates peripheral nutrient cues to serotonin-regulated fat metabolism and feeding behaviour in the nematode C. elegans (Bouagnon et al. 2019). Based on previous findings that showed that fatty acid oxidation links serotonin control of fat metabolism and feeding behaviour (Srinivasan et al. 2008), they found that intestinal peroxisomal beta-oxidation regulates serotonin signaling. Animals defective for acyl-CoA oxidase 1 (Acox1), an enzyme of the peroxisomal beta-oxidation pathway, do not show the positive effect of serotonin on feeding and egg-laying behaviors. When serotonin is added to wild type nematodes, the pharyngeal pump activity and the egg-laying rate increase, but this response was blunted in acox-1 mutant animals. To better understand the molecular mechanism underlying this phenotype, they performed transcriptomic and metabolomic studies on these animals, and found more alterations in the metabolome than in the transcriptome. Even though they could not find the exact metabolite that would be causing this alteration in serotonergic signaling, they pointed to some accumulated metabolites, such as N-acylethanolamines (from the endocannabinoid family) and ascarosides, as potential candidates for causal agents.

They also identified the cellular component of this metabolic/neural pathway. Ether-a-go-go (EAG) potassium channels in body cavity neurons (such as URX neurons) were the key cellular components of this circuit. These potassium channels modulate the excitability of neuromuscular circuits in response to nutrient scarcity, which suggest that they link internal nutritional cues and neuronal activity. RNAi of egl-2, one of these potassium channels, rescued pharyngeal pumping rate and egg-laying phenotype in worms, whereas a gain-of-function mutant of egl-2 was sufficient to mimic acox-1 mutant phenotype in terms of serotonin-induced feeding behaviour and the egg-laying defect.

 

What I liked about the study

I liked this study because they found new players in the functional connection between feeding behaviour and lipid metabolism control, and they define exciting questions in this field that need to be explored. They also proved the utility of C. elegans as a model for neurometabolic research, and report a novel role of peroxisomal metabolism in feeding behaviour regulation, which expands the myriad of functions that peroxisomes carry out. Some of the big questions now are the metabolites involved in this neurometabolic pathway and whether this mechanism is conserved in mammals.

 

Open questions:

 

• Oleic acid represses feeding behaviour in worms. Is this mediated by peroxisomal metabolism? What would happen if oleic acid is added to acox-1 mutants in terms of serotonin-regulated feeding behaviour?

 

• Fasting recovered the effect of serotonin on feeding in acox-1 mutants. That means that acox-1 is not needed for this serotonin circuit in fasting conditions. Does it mean that lipid oxidation in mitochondria is enough for the signaling of this circuit? Or that other peroxisomal enzymes are induced and then overcome acox-1 function?

 

• In C. elegans, URX neurons couple the sensing of oxygen levels to feeding behaviour and fat metabolism. Is the identity of this neural pathway known in mammals?

 

References

Bouagnon, Aude, Shubhi Srivastava, Oishika Panda, Frank C. Schroeder, Supriya Srinivasan, and Kaveh Ashrafi. 2019. “Intestinal Peroxisomal Fatty Acid β-Oxidation Regulates Neural Serotonin Signaling through a Feedback Mechanism.” BioRxiv, April, 602649. https://doi.org/10.1101/602649.

Ringstad, Niels. 2016. “A Controlled Burn: Sensing Oxygen to Tune Fat Metabolism.” Cell Reports 14 (7): 1569–70. https://doi.org/10.1016/j.celrep.2016.02.015.

Srinivasan, Supriya, Leila Sadegh, Ida C. Elle, Anne G.L. Christensen, Nils J. Faergeman, and Kaveh Ashrafi. 2008. “Serotonin Regulates C. Elegans Fat and Feeding through Independent Molecular Mechanisms.” Cell Metabolism 7 (6): 533–44. https://doi.org/10.1016/j.cmet.2008.04.012.

Witham, Emily, Claudio Comunian, Harkaranveer Ratanpal, Susanne Skora, Manuel Zimmer, and Supriya Srinivasan. 2016. “C. Elegans Body Cavity Neurons Are Homeostatic Sensors That Integrate Fluctuations in Oxygen Availability and Internal Nutrient Reserves.” Cell Reports 14 (7): 1641–54. https://doi.org/10.1016/j.celrep.2016.01.052.

Tags: behaviour, food, homeostasis, lipids, peroxisomes, serotonin

Posted on: 29th May 2019

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