TY - JOUR
T1 - Selective control of up-regulated and down-regulated genes by temporal patterns and doses of insulin
AU - Sano, Takanori
AU - Kawata, Kentaro
AU - Ohno, Satoshi
AU - Yugi, Katsuyuki
AU - Kakuda, Hiroaki
AU - Kubota, Hiroyuki
AU - Uda, Shinsuke
AU - Fujii, Masashi
AU - Kunida, Katsuyuki
AU - Hoshino, Daisuke
AU - Hatano, Atsushi
AU - Ito, Yuki
AU - Sato, Miharu
AU - Suzuki, Yutaka
AU - Kuroda, Shinya
N1 - Funding Information:
This work was supported by the Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics, CREST from the Japan Science and Technology Agency (JST), by the Japan Diabetes Foundation, and by the Ono Medical Research Foundation. K.Y. was funded by the Japan Society for the Promotion of Science (JSPS) [JSPS Grants-in-Aid for Scientific Research (KAKENHI) grant no. JP15H05582] and by the "Creation of Innovative Technology for Medical Applications Based on the Global Analyses and Regulation of Disease-Related Metabolites," PRESTO from JST. H. Kubota was funded by "Elucidation and regulation in the dynamic maintenance and transfiguration of homeostasis in living body," PRESTO from JST.
Publisher Copyright:
© 2016 The Authors, some rights reserved.
PY - 2016/11/22
Y1 - 2016/11/22
N2 - Secretion of insulin transiently increases after eating, resulting in a high circulating concentration. Fasting limits insulin secretion, resulting in a low concentration of insulin in the circulation. We analyzed transcriptional responses to different temporal patterns and doses of insulin in the hepatoma FAO cells and identified 13 up-regulated and 16 down-regulated insulin-responsive genes (IRGs). The up-regulated IRGs responded more rapidly than did the down-regulated IRGs to transient stepwise or pulsatile increases in insulin concentration, whereas the downregulated IRGs were repressed at lower concentrations of insulin than those required to stimulate the up-regulated IRGs. Mathematical modeling of the insulin response as two stages-(i) insulin signaling to transcription and (ii) transcription and mRNA stability-indicated that the first stage was the more rapid stage for the down-regulated IRGs, whereas the second stage of transcription was the more rapid stage for the up-regulated IRGs. A subset of the IRGs that were up-regulated or down-regulated in the FAO cells was similarly regulated in the livers of rats injected with a single dose of insulin. Thus, not only can cells respond to insulin but they can also interpret the intensity and pattern of signal to produce distinct transcriptional responses. These results provide insight that may be useful in treating obesity and type 2 diabetes associated with aberrant insulin production or tissue responsiveness.
AB - Secretion of insulin transiently increases after eating, resulting in a high circulating concentration. Fasting limits insulin secretion, resulting in a low concentration of insulin in the circulation. We analyzed transcriptional responses to different temporal patterns and doses of insulin in the hepatoma FAO cells and identified 13 up-regulated and 16 down-regulated insulin-responsive genes (IRGs). The up-regulated IRGs responded more rapidly than did the down-regulated IRGs to transient stepwise or pulsatile increases in insulin concentration, whereas the downregulated IRGs were repressed at lower concentrations of insulin than those required to stimulate the up-regulated IRGs. Mathematical modeling of the insulin response as two stages-(i) insulin signaling to transcription and (ii) transcription and mRNA stability-indicated that the first stage was the more rapid stage for the down-regulated IRGs, whereas the second stage of transcription was the more rapid stage for the up-regulated IRGs. A subset of the IRGs that were up-regulated or down-regulated in the FAO cells was similarly regulated in the livers of rats injected with a single dose of insulin. Thus, not only can cells respond to insulin but they can also interpret the intensity and pattern of signal to produce distinct transcriptional responses. These results provide insight that may be useful in treating obesity and type 2 diabetes associated with aberrant insulin production or tissue responsiveness.
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U2 - 10.1126/scisignal.aaf3739
DO - 10.1126/scisignal.aaf3739
M3 - Article
C2 - 27879394
AN - SCOPUS:84997221505
VL - 9
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 455
M1 - ra112
ER -