Feeding: How specific molecules can lead to overeating
A molecular pathway involving compounds found in processed foods and biogenic amines increases food intake and aging in the roundworm C. elegans.
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), UNS–CONICET, Argentina
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional Del Sur, Argentina
Toasted marshmallows, roasted nuts and fried potatoes are just a few examples of foods that owe their unique taste to a chemical reaction that produces molecules called advanced glycation end-products. These compounds form when sugars react spontaneously with proteins or lipids without the involvement of enzymes. Modern processed foods, especially those subjected to high temperatures for long periods of time – as happens with grilling, roasting or frying – are particularly high in advanced glycation end-products (Liu et al., 2020), but these compounds can also be produced in the body during metabolic processes (Reddy et al., 2022).
Advanced glycation end-products (AGEs) have been linked to several medical conditions, particularly diabetes, where they contribute to tissue damage and inflammation (Ramasamy et al., 2005). More recent research suggests that they can also increase neuronal damage and reduce the life span of roundworms (Chaudhuri et al., 2016). Now, in eLife, Pankaj Kapahi and colleagues based at various research institutes in the United States – including Muniesh Muthaiyan Shanmugam (Buck Institute for Research on Aging) as first author – report on the intriguing connection between diet, molecular signaling, feeding behavior and neurodegeneration in the roundworm C. elegans (Muthaiyan Shanmugam et al., 2023).
Shanmugam et al. compared the food intake of healthy worms and knock-out worms that lacked an enzyme called GLOD-4, which is responsible for degrading a compound known as methylglyoxal, a precursor of many AGE compounds (Chaudhuri et al., 2016). The high level of AGE compounds in the knock-out worms appeared to increase their food intake (as indicated by a high pharyngeal pumping rate). Consuming the AGE compound hydroimidazolone also caused the healthy worms to eat more. This suggests that the relationship between the accumulation of AGE compounds and over-eating could be conserved across the animal kingdom.
The experiments also showed that the response to AGE compounds is gradual, not immediate, with a pronounced increase in food intake occurring 24 hours after the introduction of hydroimidazolone. This temporal dimension makes it more difficult to understand how dietary choices impact feeding behavior over time. RNA sequencing also revealed that genes that code for neurotransmitters, and genes that code for proteins regulating feeding behavior, were upregulated in the knock-out worms.
Previous research has shown that biogenic amines – biomolecules that contain one or more amine groups – play a role in feeding behavior throughout the animal kingdom (Greer et al., 2008). Given this, and the differential expression of genes observed in the knock-out worms, Shanmugam et al. investigated how mutations in genes related to the synthesis of amines affected food intake in worms exposed to hydroimidazolone. They found that mutations in an enzyme called TDC-1 – which is responsible for synthesizing the amine tyramine, the invertebrate equivalent of adrenaline – stopped the overfeeding that is usually induced by hydroimidazolone.
Moreover, glod-4 mutant animals without tyramine had decreased damage in their nervous system and longer lifespans. This suggests that tyramine is a key regulator of overeating induced by hydroimidazolone, but more research is needed to fully understand the role of this particular amine. The negative effects of AGE compounds in the knock-out worms could be due to excessive eating triggered by tyramine, or it might be that tyramine itself is causing damage, as noted in a previous study (De Rosa et al., 2019). Additionally, two G-protein-coupled receptors that respond to tyramine were also implicated in the process.
The study also unravels a critical aspect of how AGE compounds influence feeding behavior at a molecular level. Specifically, exposure to hydroimidazolone increases the transcription of the gene that codes for the enzyme TDC-1, and this upregulation relies on the presence of a transcription factor called ELT-3 (Figure 1). This finding enriches our understanding of the mechanisms through which AGE compounds impact feeding behavior.
Figure 1
The relationship between AGE compounds and food intake.
Advanced glycation end-products (AGEs) can accumulate due to dietary intake (top left) or due to a lack of enzymes that break down their precursors (bottom left). This accumulation leads to the build-up of an AGE compound called hydroimidazolone (MG-H1), which stimulates the overexpression of tyramine through the ELT-2/GATA transcription factor pathway (top middle). The upregulation of tyramine promotes increased food intake, which, in turn, further increases the amount of hydroimidazolone in the body. This positive feedback loop, mediated by AGE compounds, ultimately reduces the lifespan of C. elegans (top right), and also accelerates neurodegeneration (bottom right).
It is becoming increasingly evident that AGE compounds actively participate in the regulation of physiological functions, rather than being passive byproducts of metabolic processes. The work of Shanmugam et al. demonstrates that, in C. elegans at least, overeating due to an accumulation of AGE compounds depends on the modulation of biogenic amine signals. This knowledge could contribute to a better understanding of a range of systemic diseases, including diabetes, obesity and various neurodegenerative disorders.
Shanmugam et al. also highlight the evolutionary importance of these processes. The changes to tyramine signaling responsible for the detrimental effects of AGE compounds in C. elegans raise the tantalizing possibility that aminergic modulation may have similar effects in humans. For example, prolonged adrenaline release in humans due to chronic stress has been associated with obesity, diabetes and premature aging (Yiallouris et al., 2019).
The work of Shanmugam et al. offers valuable insights into the interplay between dietary choices, molecular signaling and health. By unveiling a new pathway involving AGE compounds and aminergic signaling in C. elegans, this research enriches our understanding of the regulation of feeding behavior. It also encourages a re-evaluation of the impact of dietary AGE compounds on human health and motivates further exploration of their potential role in the development of chronic diseases.
References
-
Adrenal aging and its implications on stress responsiveness in humansFrontiers in Endocrinology 10:54.https://doi.org/10.3389/fendo.2019.00054
Article and author information
Author details
María Gabriela Blanco
Publication history
Copyright
© 2023, Blanco and Rayes
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 897
- views
-
- 65
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Feeding: How specific molecules can lead to overeating
eLife 12:e93090.
https://doi.org/10.7554/eLife.93090
Further reading
-
- Genetics and Genomics
Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes – most notably functional regulatory elements – in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants – at all scales, from other genetic variants and gene regulation to cell biology to organismal environment – are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.
-
- Developmental Biology
- Genetics and Genomics
Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally-induced effects on placenta development and function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm histone H3 lysine 4 tri-methylation signatures, the placenta transcriptome and cellular composition. C57BL6/J male mice were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 at promoters of genes involved in metabolism and development. Notably, sperm altered H3K4me3 was also localized at placental enhancers. Bulk RNA-sequencing on placentas revealed paternal obesity-associated sex-specific changes in expression of genes involved in hypoxic processes such as angiogenesis, nutrient transport, and imprinted genes, with a subset of deregulated genes showing changes in H3K4me3 in sperm at corresponding promoters. Paternal obesity was also linked to impaired placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity-effects on placenta development and function as one potential developmental route to offspring metabolic disease.
