Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo

Author(s)

Batista, Thiago M. ^[1] ; Garcia-Martin, Ruben ^[1] ; Cai, Weikang ^[1] ; Konishi, Masahiro ^[1] ; O'Neill, Brian T. ^{[1, 2]} ; Sakaguchi, Masaji ^{[1, 3]} ; Kim, Jong Hun ^{[4, 5]} ; Jung, Dae Young ^[4] ; Kim, Jason K. ^{[4, 6]} ; Kahn, C. Ronald ^[1]

Affiliation

^[1] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 - USA

^[2] Univ Iowa, Carver Coll Med, Fraternal Order Eagles Diabet Res Ctr, Div Endocrinol & Metab, Iowa City, IA - USA

^[3] Kumamoto Univ, Dept Metab Med, Chuo Ku, 1-1-1 Honjo, Kumamoto 8608556 - Japan

^[4] Univ Massachusetts, Sch Med, Dept Med, Program Mol Med, Worcester, MA 01655 - USA

^[5] Sungshin Univ, Dept Food Sci & Biotechnol, Seoul 01133 - South Korea

^[6] Univ Massachusetts, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Worcester, MA 01655 - USA

• Document type: Journal article
• Source: CELL REPORTS; v. 26, n. 12, p. 3429+, MAR 19 2019.
• Web of Science Citations: 5

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. (AU)

• FAPESP's process: 14/25370-8 - Characterization of human induced pluripotent stem cell (iPSC)-derived hepatocytes from insulin-resistant subjects
• Grantee: Thiago Martins Batista
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor