[SS16] Next-Generation Mathematical Biology: Where It Meets Bioinformatics

[SS16-03] Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in liver of healthy and obese mice

*Keigo Morita¹, Atsushi Hatano^1,2,3, Toshiya Kokaji^1,4, Hikaru Sugimoto¹, Takaho Tsuchiya⁵, Haruka Ozaki⁵, Riku Egami¹, Dongzi Li¹, Akira Terakawa¹, Satoshi Ohno^1,6, Hiroshi Inoue⁷, Yuka Inaba⁷, Yutaka Suzuki¹, Masaki Matsumoto², Masatomo Takahashi⁸, Yoshihiro Izumi⁸, Takeshi Bamba⁸, Akiyoshi Hirayama⁹, Tomoyoshi Soga⁹, Shinya Kuroda¹ (1. University of Tokyo (Japan), 2. Niigata University (Japan), 3. RIKEN Center for Integrative Medical Sciences (Japan), 4. Nara Institute of Science and Technology (Japan), 5. University of Tsukuba (Japan), 6. Science Tokyo (Japan), 7. Kanazawa University (Japan), 8. Kyushu University (Japan), 9. Keio Univesity (Japan))

Keywords:

transomics,metabolism,network biology,adaptation to starvation,obesity

Adaptation to starvation, one of the most essential responses for maintaining metabolic homeostasis, is a multi-molecular and temporally ordered process that could be impaired in obesity. To investigate how a healthy liver orchestrates various molecules in a temporally ccoordinated manner during starvation and how obesity disrupts this process, we measured time-series multi-omic data from the livers of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation, including metabolome, lipidome, proteome, phospho-proteome, and transcriptome data. We integrated the measured data into a transomic network comprising responsive molecules and their regulatory relationships during starvation. Our analysis revealed that metabolites, proteins, and phosphorylation events play essential roles in WT mice, whereas lipids a prominent role in ob/ob mice. We extracted a starvation-responsive metabolic network, that is a sub-network of the transomic network, and analyzed the structural properties. In WT mice, ATP and AMP, which are key energy molecules, regulated various metabolic reactions in the network as hub molecules, while neither ATP nor AMP was responsive in ob/ob mice. However, the structural properties of the network were maintained in ob/ob mice. In WT mice, molecules were temporally ordered through metabolic process by the hub molecules such as ATP and AMP, exhibiting positive or negative co-regulations with each other. In contrast, both temporal order and co-regulation were disrupted in ob/ob mice. In summary, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity.