A New Framework for Understanding Metabolism

Two papers published today in the journal Nature describe a significant advance in understanding the complex functions of the metabolic network. The research is from the lab of Marian Walhout, PhD, the Maroun Semaan Chair in Biomedical Research and chair and professor of systems biology, which has been engaged with fundamental questions of metabolism for more than a decade.  

According to Dr. Walhout, organisms constantly monitor their nutrient intake and adjust their metabolism to generate biomass and energy; their metabolism takes place through a series of chemical reactions that together make up the metabolic network. The Walhout lab has sought to understand how these reactions work together and what happens when the normal flow of information within the network is disrupted. Do cells have the capacity to find alternate routes through the network? And how do they do this? The answers to these questions have broad implications as many diseases and health-related issues such as cancer, diabetes and obesity have root causes that stem from altered metabolism. 

While single reactions and metabolic pathways have been studied in detail, it has been painstaking to determine which are active or ‘carry flux’ in a given cell, at a given moment. The first paper published today, “Systems-level design principles of metabolic rewiring in an animal” employs a systems approach to understanding the principles whereby the animal changes the flow of metabolism when metabolic reactions are disrupted. The second paper, “A systems-level, semi-quantitative landscape of metabolic flux in C. elegans,” uses data obtained from the first paper to infer the ‘natural’ wiring of the metabolic circuit in an animal, describing which reactions are active and which are turned off in a normal state.  

Both studies were enabled by “Worm Perturb-Seq” (WPS), a novel high-throughput method used to deplete the expression of around 900 metabolic genes individually in C. elegans. WPS uses RNA sequencing to unveil how changes in different parts of the metabolic network (flux) affect gene expression and shows that gene expression can be used to learn how an organism deals with alterations in its metabolism. The data accrued from this systematic study revealed a high-level model where ‘core’ metabolic functions, when depleted, are compensated for by genes with the same core metabolic function while other core metabolic functions are repressed. What Walhout and colleagues have called a “compensation-repression,” or CR model, represents a strategy used by, in this case, the worm, to monitor the state of its metabolism and adjust it at the gene regulatory level. Fascinatingly, preliminary analysis of human data indicates that the CR model may also explain perturbations in human metabolism. 

“When we analyzed the WPS data, it became clear that it was not only instrumental to understand how the animal rewires its metabolism through the compensation-repression model, but also that we could use the data to infer, by computational modeling, how the metabolic flux runs through the network, or is ‘wired,’ in the worm in its normal state,” said Walhout. “By transforming questions about metabolism into a genomics challenge, we were able to draw a ‘wiring map’ of adult worm metabolism that revealed numerous novel insights.” 

“The most exciting part of the study for me was seeing that the majority of our predictions are validated through isotope tracing experiments,” said Hefei Zhang, PhD, a postdoctoral fellow and co-first author on both papers. “Those results indicated that our concept of using molecular phenotypes to predict metabolic network wiring at systems level is really reliable.”  

Among these insights are the use of RNA as a carbon source by the organism; the use of amino acids as an energy source to fuel the tricarboxylic acid cycle; and surprisingly, that carbohydrates such as glucose, which had previously been assumed to be the major source for energy production, have a relatively minor contribution in the worm. 

“WPS and the results presented in the two studies should provide a powerful framework for similar studies in other organisms, including humans, to provide insights into healthy metabolism, as well as different diseases where metabolism runs awry,” said Walhout.  

Xuhang Li, a PhD candidate in the Walhout lab who recently completed his doctoral work and is co-first author on both papers, added, “Together, these studies establish a new paradigm for studying metabolism through the lens of genomics, enabling a systems-level understanding of metabolic dynamics.” 

Reference: Li X, Zhang H, Hodder T, et al. Systems-level design principles of metabolic rewiring in an animal. Nature. 2025. doi: 10.1038/s41586-025-08636-5

 

Zhang H, Li X, Tseyang LT, et al. A systems-level, semi-quantitative landscape of metabolic flux in C. elegans. Nature. 2025. doi: 10.1038/s41586-025-08635-6

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