ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells

Eiji Yoshihara, Zong Wei, Chun Shi Lin, Sungsoon Fang, Maryam Ahmadian, Yasuyuki Kida, Tiffany Tseng, Yang Dai, Ruth T. Yu, Christopher Liddle, Annette R. Atkins, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Summary Pancreatic β cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify estrogen-related receptor γ (ERRγ) expression as a hallmark of adult, but not neonatal β cells. Postnatal induction of ERRγ drives a transcriptional network activating mitochondrial oxidative phosphorylation, the electron transport chain, and ATP production needed to drive glucose-responsive insulin secretion. Mice deficient in β cell-specific ERRγ expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge. Notably, forced expression of ERRγ in iPSC-derived β-like cells enables glucose-responsive secretion of human insulin in vitro, obviating in vivo maturation to achieve functionality. Moreover, these cells rapidly rescue diabetes when transplanted into β cell-deficient mice. These results identify a key role for ERRγ in β cell metabolic maturation, and offer a reproducible, quantifiable, and scalable approach for in vitro generation of functional human β cell therapeutics.

Original languageEnglish (US)
Pages (from-to)622-634
Number of pages13
JournalCell Metabolism
Volume23
Issue number4
DOIs
StatePublished - Apr 12 2016

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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