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Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity

Toshiya Kokaji, Atsushi Hatano, Yuki Ito, Katsuyuki Yugi, Miki Eto, Satoshi Ohno, Masashi Fujii, Ken-ichi Hironaka, Riku Egami, Hiroshi Inoue, Shinsuke Uda, Hiroyuki Kubota, Yutaka Suzuki, Kazutaka Ikeda, Makoto Arita, Masaki Matsumoto, Keiichi I. Nakayama, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda
doi: https://doi.org/10.1101/653758
Toshiya Kokaji
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Atsushi Hatano
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2YCI Laboratory for Trans-Omics, Young Chief Investigator Program, RIKEN Center for Integrative Medical Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
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Yuki Ito
3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
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Katsuyuki Yugi
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2YCI Laboratory for Trans-Omics, Young Chief Investigator Program, RIKEN Center for Integrative Medical Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
4Institute for Advanced Biosciences, Keio University, Fujisawa, 252-8520, Japan
5PRESTO, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
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Miki Eto
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Satoshi Ohno
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Masashi Fujii
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
6Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
7Program of Mathematical and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, Kagamiyama, Higashi-hiroshima 739-8526, Japan
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Ken-ichi Hironaka
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Riku Egami
3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
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Hiroshi Inoue
8Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
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Shinsuke Uda
9Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Hiroyuki Kubota
9Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Yutaka Suzuki
3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
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Kazutaka Ikeda
10Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
11Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
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Makoto Arita
10Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
11Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
12Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo, Japan
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Masaki Matsumoto
13Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Keiichi I. Nakayama
13Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Akiyoshi Hirayama
14Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
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Tomoyoshi Soga
14Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
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Shinya Kuroda
1Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
15Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan
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  • For correspondence: skuroda@bs.s.u-tokyo.ac.jp
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Abstract

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in the healthy and obese states, we constructed and analyzed trans-omic glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multi-omic time-course data from wild-type (WT) and leptin-deficient obese (ob/ob) mice after orally administered glucose. In WT mice, metabolic reactions were rapidly regulated (within 10 minutes of oral glucose administration) primarily by glucose-responsive metabolites, especially ATP and NADP+, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-dependent glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, most rapid regulation by glucose-responsive metabolites was absent; instead, glucose administration produced slow changes in the expression of metabolic enzyme-encoding genes to alter metabolic reactions in a time scale of hours. Few common regulatory events occurred in both the healthy and obese mice. Thus, our trans-omic network analysis revealed regulation of liver metabolism in response to glucose is mediated through different mechanisms in the healthy and obese states: Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.

One Sentence Summary Rapid changes in regulatory metabolites and gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.

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Posted May 31, 2019.
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Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity
Toshiya Kokaji, Atsushi Hatano, Yuki Ito, Katsuyuki Yugi, Miki Eto, Satoshi Ohno, Masashi Fujii, Ken-ichi Hironaka, Riku Egami, Hiroshi Inoue, Shinsuke Uda, Hiroyuki Kubota, Yutaka Suzuki, Kazutaka Ikeda, Makoto Arita, Masaki Matsumoto, Keiichi I. Nakayama, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda
bioRxiv 653758; doi: https://doi.org/10.1101/653758
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Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity
Toshiya Kokaji, Atsushi Hatano, Yuki Ito, Katsuyuki Yugi, Miki Eto, Satoshi Ohno, Masashi Fujii, Ken-ichi Hironaka, Riku Egami, Hiroshi Inoue, Shinsuke Uda, Hiroyuki Kubota, Yutaka Suzuki, Kazutaka Ikeda, Makoto Arita, Masaki Matsumoto, Keiichi I. Nakayama, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda
bioRxiv 653758; doi: https://doi.org/10.1101/653758

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