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Research Article

Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

Jeffery S. Tessem, Larry G. Moss, Lily C. Chao, Michelle Arlotto, Danhong Lu, Mette V. Jensen, Samuel B. Stephens, Peter Tontonoz, Hans E. Hohmeier, and Christopher B. Newgard
PNAS first published March 24, 2014; https://doi.org/10.1073/pnas.1320953111
Jeffery S. Tessem
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
cDepartment of Pharmacology and Cancer Biology, and
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Larry G. Moss
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
dDepartment of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, NC 27704; and
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Lily C. Chao
eHoward Hughes Medical Institute and
fDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662
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Michelle Arlotto
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
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Danhong Lu
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
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Mette V. Jensen
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
cDepartment of Pharmacology and Cancer Biology, and
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Samuel B. Stephens
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
cDepartment of Pharmacology and Cancer Biology, and
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Peter Tontonoz
eHoward Hughes Medical Institute and
fDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662
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Hans E. Hohmeier
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
dDepartment of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, NC 27704; and
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Christopher B. Newgard
aSarah W. Stedman Nutrition and Metabolism Center,
bDuke Molecular Physiology Institute,
cDepartment of Pharmacology and Cancer Biology, and
dDepartment of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, NC 27704; and
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  • For correspondence: chris.newgard@duke.edu
  1. Edited by Bruce M. Spiegelman, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, and approved February 24, 2014 (received for review November 7, 2013)

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Significance

Loss of pancreatic islet β cells occurs in both major forms of diabetes, and strategies for restoring β cells are needed. The homeobox transcription factor NK6 homeobox 1 (Nkx6.1) activates β-cell proliferation and insulin secretion when overexpressed in pancreatic islets, but the molecular pathway involved in the proliferative response is unknown. We show that Nkx6.1 induces expression of orphan nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3), which stimulate proliferation via two mechanisms: (i) increased expression of the cell cycle inducers E2F transcription factor 1 and cyclin E1; and (ii) induction of anaphase-promoting complex elements, and degradation of the cell cycle inhibitor p21. These studies reveal a new bipartite pathway for activation of β-cell proliferation that could guide development of therapeutic strategies for diabetes.

Abstract

Loss of functional β-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces β-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3) orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F transcription factor 1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including ubiquitin-conjugating enzyme E2C, resulting in degradation of the cell cycle inhibitor p21. These studies identify a unique bipartite pathway for activation of β-cell proliferation, suggesting several unique targets for expansion of functional β-cell mass.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: chris.newgard{at}duke.edu.
  • Author contributions: J.S.T., L.G.M., P.T., H.E.H., and C.B.N. designed research; J.S.T., L.C.C., M.A., D.L., M.V.J., S.B.S., and H.E.H. performed research; J.S.T., L.C.C., M.A., S.B.S., and P.T. contributed new reagents/analytic tools; J.S.T., L.G.M., H.E.H., and C.B.N. analyzed data; and J.S.T. and C.B.N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE55079).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1320953111/-/DCSupplemental.

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Nr4a receptors regulate islet β-cell expansion
Jeffery S. Tessem, Larry G. Moss, Lily C. Chao, Michelle Arlotto, Danhong Lu, Mette V. Jensen, Samuel B. Stephens, Peter Tontonoz, Hans E. Hohmeier, Christopher B. Newgard
Proceedings of the National Academy of Sciences Mar 2014, 201320953; DOI: 10.1073/pnas.1320953111

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Nr4a receptors regulate islet β-cell expansion
Jeffery S. Tessem, Larry G. Moss, Lily C. Chao, Michelle Arlotto, Danhong Lu, Mette V. Jensen, Samuel B. Stephens, Peter Tontonoz, Hans E. Hohmeier, Christopher B. Newgard
Proceedings of the National Academy of Sciences Mar 2014, 201320953; DOI: 10.1073/pnas.1320953111
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