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

Cell Rep. 2019 Mar 19;26(12):3429-3443.e3. doi: 10.1016/j.celrep.2019.02.081.

Authors

Affiliations

¹ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
² Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
³ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuoku, Kumamoto 860-8556, Japan.
⁴ Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Food Science and Biotechnology, Sungshin University, Seoul 01133, Republic of Korea.
⁵ Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁶ Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁷ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: c.ronald.kahn@joslin.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Glucose Clamp Technique
Hepatocytes / metabolism*
Insulin / pharmacology*
Insulin Resistance*
Liver / metabolism*
Male
Mice
RNA, Long Noncoding / metabolism*
Transcription Factors / metabolism*

Substances

Insulin
RNA, Long Noncoding
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding