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
Affiliations
Thiago M. Batista
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Ruben Garcia-Martin
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Weikang Cai
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Masahiro Konishi
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Brian T. O’Neill
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
Masaji Sakaguchi
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
Jong Hun Kim
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
Dae Young Jung
Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
Jason K. Kim
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
C. Ronald Kahn
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Summary: 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. : 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. Keywords: insulin action, gene expression, skeletal muscle, mitochondria, liver, diabetes, non-coding RNAs, fatty acid oxidation
