biostudies-literatureYoshihara ENIDDK NIH HHSNIEHS NIH HHSNHLBI NIH HHSNCI NIH HHS622-34https://www.ebi.ac.uk/biostudies/studies/S-EPMC4832237biostudies-literatureUnknown23(4)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.Cell metabolismERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.PMC4832237R01 HL105278R37 DK057978R01 DK057978HL105278P01 HL088093P42 ES010337DK090962R24 DK090962P30 CA014195HL088093P30 DK063491ES010337DK057978Kida YAtkins ARWei ZDai YYoshihara EDownes MAhmadian MLin CSTseng TLiddle CFang SYu RTEvans RMfalseERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.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.2016-01-01T00:00:00Z2016 Apr2026-04-12T23:54:39.601Z2019-03-27T02:11:35ZS-EPMC48322372707607710.1016/j.cmet.2016.03.005