E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance

  • Cell Rep. 2022 Oct 4;41(1):111436. doi: 10.1016/j.celrep.2022.111436.
Jun Shirakawa  1 ,  Yu Togashi  2 ,  Giorgio Basile  3 ,  Tomoko Okuyama  2 ,  Ryota Inoue  4 ,  Megan Fernandez  3 ,  Mayu Kyohara  2 ,  Dario F De Jesus  3 ,  Nozomi Goto  2 ,  Wei Zhang  3 ,  Takahiro Tsuno  4 ,  Tatsuya Kin  5 ,  Hui Pan  6 ,  Jonathan M Dreyfuss  6 ,  A M James Shapiro  5 ,  Peng Yi  3 ,  Yasuo Terauchi  2 ,  Rohit N Kulkarni  7
Affiliations
  • 1. Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA; Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan. Electronic address: [email protected].
  • 2. Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan.
  • 3. Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 4. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan.
  • 5. Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
  • 6. Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
  • 7. Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 36198264 DOI: 10.1016/j.celrep.2022.111436
Abstract

Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute Insulin resistance induced by S961, a pharmacological Insulin Receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of Insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest Insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

Keywords
CP: Metabolism; E2F1; acute insulin resistance; adipocytes; compensation; human beta cells; insulin receptor; inter-organ communication; transcription factor; β cell proliferation.
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