Kinetic Trans-omic Analysis Reveals Key Regulatory Mechanisms for Insulin-Regulated Glucose Metabolism in Adipocytes

Satoshi Ohno; Lake-Ee Quek; James R Krycer; Katsuyuki Yugi; Akiyoshi Hirayama; Satsuki Ikeda; Futaba Shoji; Kumi Suzuki; Tomoyoshi Soga; David E James; Shinya Kuroda

doi:10.1016/j.isci.2020.101479

Kinetic Trans-omic Analysis Reveals Key Regulatory Mechanisms for Insulin-Regulated Glucose Metabolism in Adipocytes

iScience. 2020 Aug 20;23(9):101479. doi: 10.1016/j.isci.2020.101479. eCollection 2020 Sep 25.

Authors

Satoshi Ohno^{1

2}, Lake-Ee Quek^{3

4}, James R Krycer^{3

5}, Katsuyuki Yugi^{2

6

7

8}, Akiyoshi Hirayama^{8

9}, Satsuki Ikeda⁸, Futaba Shoji⁸, Kumi Suzuki⁸, Tomoyoshi Soga^{8

9}, David E James^{3

5

10}, Shinya Kuroda^{1

2

11

12}

Affiliations

¹ Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan.
² Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia.
⁵ School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
⁶ Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁷ PRESTO, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁸ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
⁹ AMED-CREST, AMED, 1-7-1 Otemachi, Chiyoda-Ku, Tokyo 100-0004, Japan.
¹⁰ Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
¹¹ 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.
¹² Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan.

Abstract

Insulin regulates glucose metabolism through thousands of regulatory mechanisms; however, which regulatory mechanisms are keys to control glucose metabolism remains unknown. Here, we performed kinetic trans-omic analysis by integrating isotope-tracing glucose flux and phosphoproteomic data from insulin-stimulated adipocytes and built a kinetic mathematical model to identify key allosteric regulatory and phosphorylation events for enzymes. We identified nine reactions regulated by allosteric effectors and one by enzyme phosphorylation and determined the regulatory mechanisms for three of these reactions. Insulin stimulated glycolysis by promoting Glut4 activity by enhancing phosphorylation of AS160 at S595, stimulated fatty acid synthesis by promoting Acly activity through allosteric activation by glucose 6-phosphate or fructose 6-phosphate, and stimulated glutamate synthesis by alleviating allosteric inhibition of Gls by glutamate. Most of glycolytic reactions were regulated by amounts of substrates and products. Thus, phosphorylation or allosteric modulator-based regulation of only a few key enzymes was sufficient to change insulin-induced metabolism.

Keywords: Biological Sciences; Mathematical Biosciences; Metabolic Flux Analyisis; Metabolomics; Omics; Proteomics; Systems Biology.