Obesity alters the rhythm of liver’s starvation response

Researchers led by Keigo Morita and Shinya Kuroda of the University of Tokyo have revealed a temporal disruption in the metabolism of obese mice when adapting to starvation despite no significant structural disruptions in the molecular network. This is a breakthrough discovery as research including the temporal dimension in biology has been notoriously laborious and extracting systematic insight from big data has been difficult. Thus, this study paves the way for further research into more general metabolic processes, such as food intake and disease progression. The findings were published in the journal Science Signaling.

Living beings need to continuously extract energy from "food" and distribute it within the body to stay alive, that is keep their metabolisms running so that their bodies are in an optimal range called "homeostatis." Starvation is one of the most severe disruptions to this system. When adapting to starvation, the liver, which plays a central role in metabolism, coordinates not just which but also when molecules need to take action.

Molecules inside cells form a large network, containing a small number of molecules regulating many metabolic reactions called hub molecules. However, a systematic understanding of the temporal coordination of molecules in the liver had been elusive due to the lack of comprehensive time-series data during starvation."

Shinya Kuroda, principal investigator, University of Tokyo

The researchers set out to fill the gap by comparing the livers of healthy and obese mice. Their measures showed a clear difference between the hub molecules of healthy and obese liver cells. The former contained the energy-related molecules ATP and AMP, but the latter did not. Such a clear difference between hub molecules could have structurally disrupted the molecular network. However, the researchers did not find such disruptions, so they investigated the temporal dimension.

"We comprehensively measured the time courses of various molecules," says Kuroda, "and found that hub molecules in healthy livers responded to starvation more rapidly than other molecules. This suggested a well-controlled temporal order of the molecular networks in healthy livers during starvation. On the other hand, this coordination disappeared in the liver of obese mice."

In other words, even though the structure of the molecular network during starvation remained robust, it became temporally vulnerable to obesity. The method that led to this discovery, combining structural and temporal analysis of the intracellular molecular network, can be applied to other studies that include data sets from multiple "omes" such as the genome or the microbiome, opening avenues for further research. Kuroda describes their next project.

"Our approach successfully described the global landscape of adaptation to starvation, a complicated biological phenomenon. We would like to generalize our insights of the metabolic network during starvation to the metabolic network during food intake or disease progression."