Journal article
Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo
Cell reports (Cambridge), Vol.26(12), pp.3429-3443.e3
03/19/2019
DOI: 10.1016/j.celrep.2019.02.081
PMCID: PMC6543850
PMID: 30893613
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.
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•Physiological insulin regulates a broad transcriptional network in muscle and liver•In addition to mRNA of coding genes, insulin regulates mRNA splicing and lncRNAs•Insulin-regulated gene expression involves multiple transcriptional regulators•The insulin-suppressed lncRNA Gm15441 regulates fatty acid oxidation in hepatocytes
Batista et al. demonstrate potent transcriptional remodeling by physiological insulin action in skeletal muscle and liver, involving interrelated networks of protein-coding genes, transcription factors, and long non-coding RNAs (lncRNAs). From an array of metabolically sensitive lncRNAs, Gm15441 is identified as a regulator of fatty acid oxidation in hepatocytes.
Details
- Title: Subtitle
- Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo
- Creators
- Thiago M. Batista - Joslin Diabetes CenterRuben Garcia-Martin - Joslin Diabetes CenterWeikang Cai - Joslin Diabetes CenterMasahiro Konishi - Joslin Diabetes CenterBrian T. O’Neill - Joslin Diabetes CenterMasaji Sakaguchi - Joslin Diabetes CenterJong Hun Kim - Sungshin Women's UniversityDae Young Jung - University of Massachusetts Chan Medical SchoolJason K. Kim - University of Massachusetts Chan Medical SchoolC. Ronald Kahn - Joslin Diabetes Center
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.26(12), pp.3429-3443.e3
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2019.02.081
- PMID
- 30893613
- PMCID
- PMC6543850
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: R37DK031036, R01DK033201, P30DK036836, 5U2C-DK093000; name: Mary K. Iacocca Professorship; name: Sao Paulo Research Foundation, award: 2014/25370-8; DOI: 10.13039/501100001659, name: Deutsche Forschungsgemeinschaft, award: GA 2426/1-1, K08DK100543, R03DK112003; DOI: 10.13039/100000062, name: NIDDK; DOI: 10.13039/100000002, name: NIH
- Language
- English
- Date published
- 03/19/2019
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984360040502771
Metrics
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