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A recent study led by researchers Keigo Morita and Shinya Kuroda from the University of Tokyo has unveiled significant insights into the metabolic changes that occur in obese mice when faced with starvation, despite the absence of major structural changes within their molecular networks. This finding represents a significant advancement, as incorporating the temporal aspect of biological processes has historically been challenging, making it difficult to derive systematic insights from large datasets. The results of this study, which could inform broader metabolic research, are documented in the journal Science Signaling.
To maintain life, organisms must extract energy from food and effectively distribute this energy within their bodies, a process essential for sustaining metabolism and achieving a stable internal environment known as “homeostasis.” Starvation creates one of the most extreme challenges to this homeostatic balance. The liver plays a pivotal role in metabolic regulation, not only determining which molecules are activated but also the timing of these actions in response to starvation.
“Inside cells, molecules create an extensive network, with certain key molecules known as hub molecules that regulate various metabolic reactions,” explained Kuroda, the principal investigator of the study. “However, understanding how these molecules coordinate over time, particularly in the liver during starvation, has been a difficult task due to the lack of detailed time-series data.”
To address this knowledge gap, the research team compared liver samples from healthy and obese mice. Their analysis revealed distinct differences in the hub molecules found in healthy versus obese liver cells. Healthy livers exhibited energy-related molecules such as ATP and AMP, which were absent in the livers of obese mice. Whereas one might expect that these differences would indicate disruptions in the structural integrity of the molecular network, the researchers found no such disruptions, prompting them to explore the temporal aspect of the networks instead.
“By performing comprehensive time-course measurements of various molecules, we discovered that healthy liver hub molecules react to starvation more swiftly than their counterparts,” Kuroda noted. “This indicated a precise temporal regulation within the molecular networks of healthy livers during starvation, which was notably absent in the livers of obese mice.”
Essentially, while the overall structure of the molecular network remained intact, obesity rendered these networks vulnerable in terms of their timing during starvation adaptations. The methodology that facilitated this discovery—an integration of structural and temporal analyses of the intracellular molecular landscape—opens the door for potential applications in other studies that encompass various biological “omes,” such as genomic or microbiomic datasets, which could vastly enrich ongoing research efforts. Kuroda elaborated on future directions for their work.
“Our research has successfully outlined the complex biological response to starvation,” he stated. “We aim to extend our findings on the metabolic network under starvation conditions to explore its dynamics during food intake phases and in the context of disease progression.”
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