Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks

Kentaro Kawata, Atsushi Hatano, Katsuyuki Yugi, Hiroyuki Kubota, Takanori Sano, Masashi Fujii, Yoko Tomizawa, Toshiya Kokaji, Kaori Y. Tanaka, Shinsuke Uda, Yutaka Suzuki, Masaki Matsumoto, Keiichi I. Nakayama, Kaori Saitoh, Keiko Kato, Ayano Ueno, Maki Ohishi, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda

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Abstract

The concentrations of insulin selectively regulate multiple cellular functions. To understand how insulin concentrations are interpreted by cells, we constructed a trans-omic network of insulin action in FAO hepatoma cells using transcriptomic data, western blotting analysis of signaling proteins, and metabolomic data. By integrating sensitivity into the trans-omic network, we identified the selective trans-omic networks stimulated by high and low doses of insulin, denoted as induced and basal insulin signals, respectively. The induced insulin signal was selectively transmitted through the pathway involving Erk to an increase in the expression of immediate-early and upregulated genes, whereas the basal insulin signal was selectively transmitted through a pathway involving Akt and an increase of Foxo phosphorylation and a reduction of downregulated gene expression. We validated the selective trans-omic network in vivo by analysis of the insulin-clamped rat liver. This integrated analysis enabled molecular insight into how liver cells interpret physiological insulin signals to regulate cellular functions.

Original languageEnglish
Pages (from-to)212-229
Number of pages18
JournaliScience
Volume7
DOIs
Publication statusPublished - Sep 28 2018

All Science Journal Classification (ASJC) codes

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    Kawata, K., Hatano, A., Yugi, K., Kubota, H., Sano, T., Fujii, M., Tomizawa, Y., Kokaji, T., Tanaka, K. Y., Uda, S., Suzuki, Y., Matsumoto, M., Nakayama, K. I., Saitoh, K., Kato, K., Ueno, A., Ohishi, M., Hirayama, A., Soga, T., & Kuroda, S. (2018). Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks. iScience, 7, 212-229. https://doi.org/10.1016/j.isci.2018.07.022