Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity

Yunfan Bai; Keigo Morita; Toshiya Kokaji; Atsushi Hatano; Satoshi Ohno; Riku Egami; Yifei Pan; Dongzi Li; Katsuyuki Yugi; Saori Uematsu; Hiroshi Inoue; Yuka Inaba; Yutaka Suzuki; Masaki Matsumoto; Masatomo Takahashi; Yoshihiro Izumi; Takeshi Bamba; Akiyoshi Hirayama; Tomoyoshi Soga; Shinya Kuroda

doi:10.1016/j.isci.2024.109121

Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity

iScience. 2024 Feb 26;27(3):109121. doi: 10.1016/j.isci.2024.109121. eCollection 2024 Mar 15.

Authors

Yunfan Bai^{1

2}, Keigo Morita², Toshiya Kokaji^{2

3}, Atsushi Hatano⁴, Satoshi Ohno^{2

5

6}, Riku Egami¹, Yifei Pan¹, Dongzi Li², Katsuyuki Yugi^{2

7

8

9}, Saori Uematsu¹, Hiroshi Inoue¹⁰, Yuka Inaba¹⁰, Yutaka Suzuki¹, Masaki Matsumoto⁴, Masatomo Takahashi¹¹, Yoshihiro Izumi¹¹, Takeshi Bamba¹¹, Akiyoshi Hirayama¹², Tomoyoshi Soga¹², Shinya Kuroda^{1

2}

Affiliations

¹ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.
² Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Data Science Center, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, Japan.
⁴ Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.
⁵ Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
⁶ Department of AI Systems Medicine, M&D Data Science Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
⁷ Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁸ Institute for Advanced Biosciences, Keio University, Fujisawa 252-8520, Japan.
⁹ Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
¹⁰ Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
¹¹ Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
¹² Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.

Abstract

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

Keywords: Biological sciences; Metabolomics; Physiology; Proteomics; Transcriptomics.