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Cell Metab. 2016 Apr 12;23(4):622-34. doi: 10.1016/j.cmet.2016.03.005.

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

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; College of Life Sciences, Sejong University, Seoul 143-762, Korea.
3
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba 305-8562, Japan.
4
Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, NSW 2006, Australia.
5
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
6
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.

Abstract

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.

PMID:
27076077
PMCID:
PMC4832237
DOI:
10.1016/j.cmet.2016.03.005
[Indexed for MEDLINE]
Free PMC Article

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