Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo

Thiago M. Batista; Ruben Garcia-Martin; Weikang Cai; Masahiro Konishi; Brian T. O'Neill; Masaji Sakaguchi; Jong Hun Kim; Dae Young Jung; Jason K. Kim; C. Ronald Kahn

doi:10.1016/j.celrep.2019.02.081

Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo

Thiago M. Batista, Ruben Garcia-Martin, Weikang Cai, Masahiro Konishi, Brian T. O'Neill, Masaji Sakaguchi, Jong Hun Kim, Dae Young Jung, Jason K. Kim, C. Ronald Kahn

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.

Original language	English
Pages (from-to)	3429-3443.e3
Journal	Cell Reports
Volume	26
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2019.02.081
State	Published - Mar 19 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

Funding

This work was supported by NIH grants R37DK031036, R01DK033201 (to C.R.K.), P30DK036836 (to Joslin Diabetes Center), and 5U2C-DK093000 (to J.K.K.) and the Mary K. Iacocca Professorship (to C.R.K.). T.M.B. was partially supported by a grant from Sao Paulo Research Foundation (2014/25370-8). R.G.M. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (GA 2426/1-1). B.T.O. was funded by a K08 training award (K08DK100543) and an R03 award (R03DK112003) from the NIDDK of the NIH. We thank Jonathan M. Dreyfuss and Hui Pan from Joslin Diabetes Center DRC Genomics and Bioinformatics Core for assistance with data analysis. This work was supported by NIH grants R37DK031036 , R01DK033201 (to C.R.K.), P30DK036836 (to Joslin Diabetes Center), and 5U2C-DK093000 (to J.K.K.) and the Mary K. Iacocca Professorship (to C.R.K.). T.M.B. was partially supported by a grant from Sao Paulo Research Foundation ( 2014/25370-8 ). R.G.M. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship ( GA 2426/1-1 ). B.T.O. was funded by a K08 training award ( K08DK100543 ) and an R03 award ( R03DK112003 ) from the NIDDK of the NIH . We thank Jonathan M. Dreyfuss and Hui Pan from Joslin Diabetes Center DRC Genomics and Bioinformatics Core for assistance with data analysis.

Funders	Funder number
National Institutes of Health (NIH)	5U2C-DK093000
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases	K08DK100543, P30DK036836, R01DK031036, R03DK112003, R01DK033201
National Institute of Diabetes and Digestive and Kidney Diseases
Joslin Diabetes Center
Deutsche Forschungsgemeinschaft	GA 2426/1-1
Deutsche Forschungsgemeinschaft
Fundação de Amparo à Pesquisa do Estado de São Paulo	2014/25370-8
Fundação de Amparo à Pesquisa do Estado de São Paulo
Norges Idrettshøgskole

Keywords

diabetes
fatty acid oxidation
gene expression
insulin action
liver
mitochondria
non-coding RNAs
skeletal muscle

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.02.081

Cite this

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title = "Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo",

abstract = "Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.",

keywords = "diabetes, fatty acid oxidation, gene expression, insulin action, liver, mitochondria, non-coding RNAs, skeletal muscle",

author = "Batista, {Thiago M.} and Ruben Garcia-Martin and Weikang Cai and Masahiro Konishi and O'Neill, {Brian T.} and Masaji Sakaguchi and Kim, {Jong Hun} and Jung, {Dae Young} and Kim, {Jason K.} and Kahn, {C. Ronald}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

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doi = "10.1016/j.celrep.2019.02.081",

language = "English",

volume = "26",

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AU - Batista, Thiago M.

AU - Garcia-Martin, Ruben

AU - Cai, Weikang

AU - Konishi, Masahiro

AU - O'Neill, Brian T.

AU - Sakaguchi, Masaji

AU - Kim, Jong Hun

AU - Jung, Dae Young

AU - Kim, Jason K.

AU - Kahn, C. Ronald

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.

AB - Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.

KW - diabetes

KW - fatty acid oxidation

KW - gene expression

KW - insulin action

KW - liver

KW - mitochondria

KW - non-coding RNAs

KW - skeletal muscle

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SP - 3429-3443.e3

JO - Cell Reports

JF - Cell Reports

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ER -

Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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