E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance
Jun Shirakawa,
Yu Togashi,
Giorgio Basile,
Tomoko Okuyama,
Ryota Inoue,
Megan Fernandez,
Mayu Kyohara,
Dario F. De Jesus,
Nozomi Goto,
Wei Zhang,
Takahiro Tsuno,
Tatsuya Kin,
Hui Pan,
Jonathan M. Dreyfuss,
A.M. James Shapiro,
Peng Yi,
Yasuo Terauchi,
Rohit N. Kulkarni
Affiliations
Jun Shirakawa
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; Corresponding author
Yu Togashi
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
Giorgio Basile
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
Tomoko Okuyama
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
Ryota Inoue
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan
Megan Fernandez
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
Mayu Kyohara
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
Dario F. De Jesus
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
Nozomi Goto
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
Wei Zhang
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
Takahiro Tsuno
Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan
Tatsuya Kin
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
Hui Pan
Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Jonathan M. Dreyfuss
Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
A.M. James Shapiro
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
Peng Yi
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
Yasuo Terauchi
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
Rohit N. Kulkarni
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; Corresponding author
Summary: 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.