Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver

Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (<i>ob</i>/<i>ob</i>) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in <i>ob</i>/<i>ob</i> mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in <i>ob</i>/<i>ob</i> mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.

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Journal
Science Signaling
Published
2025-04-22
DOI
https://doi.org/10.1126/scisignal.ads2547
Citations
2
Primary Topic
Adipose Tissue and Metabolism
Type
article
Field-Weighted Citation Impact
2.33
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article

Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver

Hiroshi Inoue, Toshiya Kokaji, D.F. Li, Yutaka Suzuki et al.
2 citations
Science Signaling
Adipose Tissue and Metabolism
2.33
article

Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver

Hiroshi Inoue, Toshiya Kokaji, D.F. Li, Yutaka Suzuki, Masatomo Takahashi, Akira Terakawa, Shinya Kuroda, Tomoyoshi Soga, Riku Egami, Masaki Matsumoto, Akiyoshi Hirayama, Satoshi Ohno, Hikaru Sugimoto, Y. Inaba, Keigo Morita, Haruka Ozaki, Takaho Tsuchiya, Atsushi Hatano, Takeshi Bamba, Yoshihiro Izumi
article en
2 citations

Abstract

Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (<i>ob</i>/<i>ob</i>) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in <i>ob</i>/<i>ob</i> mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in <i>ob</i>/<i>ob</i> mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.

Science SignalingVol. 18(883)
Kanazawa University (JP), Kyushu University (JP), University of Tsukuba (JP), Keio University (JP), Cardiovascular Institute Hospital (JP), RIKEN Center for Integrative Medical Sciences (JP), Artificial Intelligence in Medicine (Canada) (CA), Niigata University (JP), The University of Tokyo (JP), Nara Institute of Science and Technology (JP)
Openalex Percentile: Top 13%
Adipose Tissue and Metabolism
2.33
DOISourceOpenAlex
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