Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism
James R. Krycer,
Katsuyuki Yugi,
Akiyoshi Hirayama,
Daniel J. Fazakerley,
Lake-Ee Quek,
Richard Scalzo,
Satoshi Ohno,
Mark P. Hodson,
Satsuki Ikeda,
Futaba Shoji,
Kumi Suzuki,
Westa Domanova,
Benjamin L. Parker,
Marin E. Nelson,
Sean J. Humphrey,
Nigel Turner,
Kyle L. Hoehn,
Gregory J. Cooney,
Tomoyoshi Soga,
Shinya Kuroda,
David E. James
Affiliations
James R. Krycer
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
Katsuyuki Yugi
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; YCI Laboratory for Trans-Omics, Young Chief Investigator Program, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; PRESTO, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Akiyoshi Hirayama
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Chiyoda-Ku, Tokyo 100-0004, Japan
Daniel J. Fazakerley
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
Lake-Ee Quek
Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia; School of Mathematics and Statistics, The University of Sydney, Sydney NSW 2006, Australia
Richard Scalzo
Centre for Translational Data Science, University of Sydney, Sydney, NSW 2006, Australia
Satoshi Ohno
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Mark P. Hodson
Metabolomics Australia Queensland Node, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia; School of Pharmacy, Faculty of Health and Behavioural Sciences, University of Queensland, Brisbane, QLD 4072, Australia; Metabolomics Research Laboratory, Victor Chang Innovation Centre, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
Satsuki Ikeda
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Futaba Shoji
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Kumi Suzuki
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Westa Domanova
Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia; School of Physics, University of Sydney, Sydney, NSW 2006, Australia
Benjamin L. Parker
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
Marin E. Nelson
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
Sean J. Humphrey
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
Nigel Turner
School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Kyle L. Hoehn
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Gregory J. Cooney
Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
Tomoyoshi Soga
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Chiyoda-Ku, Tokyo 100-0004, Japan
Shinya Kuroda
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan; CREST, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
David E. James
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
Summary: Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to “pull” glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism. : Krycer et al. explore how insulin regulates adipocyte metabolism. It is widely held that energy storage (anabolism) occurs as a substrate accumulates. However, using dynamic tracer metabolomics and overlaying phosphoproteomics data, they find that insulin signaling triggers anabolism before substrates accumulate, creating a “demand-driven” system to prime adipocytes for glucose metabolism. Keywords: adipocyte, insulin, glucose, metabolomics, metabolic tracer, metabolic priming
