title: ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.
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.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshihara
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Zong
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Chun Shi
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; College of Life Sciences, Sejong University, Seoul 143-762, Korea.
authors.forename: Sungsoon
authors.initials: S
authors.lastname: Fang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadian
authors.affiliation: 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.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tseng
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: 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.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D005947:Glucose / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C490917:ESRRG protein, human; C490916:Esrrg protein, mouse; D007328:Insulin; D011960:Receptors, Estrogen; D005947:Glucose