Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans
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eLife assessment
The work, which examines how Advanced Glycation End-products (AGEs), commonly found in processed and other cooked foods, affect eating behavior and signaling in the nematode C. elegans, is in a fundamentally important area of research with clear translational potential for humans. Some aspects of the manuscript are compelling, including the well-characterized assays on food intake, while other aspects are still incomplete, such as the mechanistic work on the neural network responsible for the response to AGEs.
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Abstract
The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming advanced glycation end-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1 -tyramine- tyra-2/ser-2 signaling as an essential pathway mediating AGE (MG-H1)-induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Furthermore, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans , we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGE-rich diets.
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eLife assessment
The work, which examines how Advanced Glycation End-products (AGEs), commonly found in processed and other cooked foods, affect eating behavior and signaling in the nematode C. elegans, is in a fundamentally important area of research with clear translational potential for humans. Some aspects of the manuscript are compelling, including the well-characterized assays on food intake, while other aspects are still incomplete, such as the mechanistic work on the neural network responsible for the response to AGEs.
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Reviewer #1 (Public Review):
In this work the authors study the effects of the accumulation of endogenously produced Advanced Glycation End-products (AGEs) on feeding behaviors in C. elegans. AGEs are produced during the metabolism of all organisms, and also, they are produced by the food industry through Mainard reactions. In this sense, the objectives of this study are not only to provide basic information relevant to phenomena that are likely to be conserved throughout the animal kingdom but also to provide information that could be important in human health for the understanding of disorders caused by the consumption of processed foods.
The methodology includes as read out very robust and supercharacterized assays of food intake in C. elegans, such as pharyngeal pumping and food depletion.
As a general evaluation of the manuscript, …Reviewer #1 (Public Review):
In this work the authors study the effects of the accumulation of endogenously produced Advanced Glycation End-products (AGEs) on feeding behaviors in C. elegans. AGEs are produced during the metabolism of all organisms, and also, they are produced by the food industry through Mainard reactions. In this sense, the objectives of this study are not only to provide basic information relevant to phenomena that are likely to be conserved throughout the animal kingdom but also to provide information that could be important in human health for the understanding of disorders caused by the consumption of processed foods.
The methodology includes as read out very robust and supercharacterized assays of food intake in C. elegans, such as pharyngeal pumping and food depletion.
As a general evaluation of the manuscript, I think the authors could provide more detailed mechanistic information about how MGH-1 acts on the tyraminergic pathway to potentiate food intake. While they find important players, they do not quite find how these players interact with each other, nor which cells or neural circuits are governing the processes described.In summary, I consider the initial objective of the manuscript to be extremely significant, but I believe it falls short in the mechanistic explanation of the observations described.
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Reviewer #2 (Public Review):
General description:
This study elucidates how Advanced Glycation End-products (AGE), found in processed food and endogenously, drive food intake and cause some of the pathophysiological defects associated with metabolic disease. In their previous C. elegans study, the authors found that glod-4 mutants, animals that lack glyoxalase activity and thus accumulate AGEs, eat more and share some of the pathophysiological effects seen in metabolic disease. In this study, they identify a specific AGE, hydroimidazolone (MG-H1), that is sufficient to increase feeding, similar to what was previously observed in the glod-4 mutants. Gene expression studies then show expression changes in several neurotransmitter and eating genes, including the tyramine decarboxylase gene tdc-1 and its receptor. Measuring eating behaviors …Reviewer #2 (Public Review):
General description:
This study elucidates how Advanced Glycation End-products (AGE), found in processed food and endogenously, drive food intake and cause some of the pathophysiological defects associated with metabolic disease. In their previous C. elegans study, the authors found that glod-4 mutants, animals that lack glyoxalase activity and thus accumulate AGEs, eat more and share some of the pathophysiological effects seen in metabolic disease. In this study, they identify a specific AGE, hydroimidazolone (MG-H1), that is sufficient to increase feeding, similar to what was previously observed in the glod-4 mutants. Gene expression studies then show expression changes in several neurotransmitter and eating genes, including the tyramine decarboxylase gene tdc-1 and its receptor. Measuring eating behaviors in animals carrying mutations in tyramine signalling genes they show that tyramine signaling system is required for the behavioral and pathophysiological effects of MG-H1. Finally, they show that the transcription factor elt-3 controls the expression of tyramine signaling components and thus is also required for the response to MG-H1.Strength: Strengths of the paper include the elegant approach to study how toxic metabolites affect physiology and behavior in vivo. The logic behind the study is easy to follow and the paper is clearly written.
Weakness: The main weakness is that the genetic studies were generally only carried out with a single mutation that was not rescued. To corroborate the requirement of tdc-1 and elt-3 for the response to MG-H1, the results should be repeated either in a rescue strain or using a different allele. Some of the effects are subtle and there is the danger of them being caused by background mutations.
Impact: The occurrence of metabolites like AGEs in either processed food or endogenously is a topic that is not well investigated despite its general importance. In this study the authors show the functional consequences of a non-enzymatically generated metabolite and how it exerts its toxicity.
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Reviewer #3 (Public Review):
This manuscript studied an interesting topic: the maillard reaction, catalyzed by glyoxalases, converts α-dicarbonyl compounds to Advanced Glycation End-products (AGEs). glod-4 is one of the glyoxalases and MG-H1 is one of AGEs which is converted from methylglyoxal (MGO). The authors discovered that both glyoxalase glod-4 KO and supplementation of MG-H1 increased pumping rates in C. elegans. MG-H1 mediated pumping rates increase is dependent on glod-4. The authors further found that tyramine synthease tdc-1 and two of the tyramine receptors ser-2 and tyra-2 are required for the increased pumping by glod-4 knockout or MG-H1. They also found the transcriptional factor elt-3 is required for pumping increase by MG-H1 and glod-4 KO, and also regulates tdc-1 transcriptional level. Lastly, they found that tdc-1 and …
Reviewer #3 (Public Review):
This manuscript studied an interesting topic: the maillard reaction, catalyzed by glyoxalases, converts α-dicarbonyl compounds to Advanced Glycation End-products (AGEs). glod-4 is one of the glyoxalases and MG-H1 is one of AGEs which is converted from methylglyoxal (MGO). The authors discovered that both glyoxalase glod-4 KO and supplementation of MG-H1 increased pumping rates in C. elegans. MG-H1 mediated pumping rates increase is dependent on glod-4. The authors further found that tyramine synthease tdc-1 and two of the tyramine receptors ser-2 and tyra-2 are required for the increased pumping by glod-4 knockout or MG-H1. They also found the transcriptional factor elt-3 is required for pumping increase by MG-H1 and glod-4 KO, and also regulates tdc-1 transcriptional level. Lastly, they found that tdc-1 and the two tyramine receptors mutants rescue the shorter lifespan of glod-4 and neuronal loss in glod-4.
The topic is interesting, and it is a good design to show mechanistic function of neurotransmitter in regulating tasty AGEs in a model organism. Most of the results are supported by the data.
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