ERRgamma Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive beta Cells.

Journal: 
Cell Metab
Publication Year: 
2016
Authors: 
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
PubMed link: 
27076077
Public Summary: 
Pancreatic beta cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify estrogen-related receptor gamma (ERRgamma) expression as a hallmark of adult, but not neonatal beta cells. Postnatal induction of ERRgamma 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 beta cell-specific ERRgamma expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge. Notably, forced expression of ERRgamma in iPSC-derived beta-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 beta cell-deficient mice. These results identify a key role for ERRgamma in beta cell metabolic maturation, and offer a reproducible, quantifiable, and scalable approach for in vitro generation of functional human beta cell therapeutics.
Scientific Abstract: 
Pancreatic beta cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify estrogen-related receptor gamma (ERRgamma) expression as a hallmark of adult, but not neonatal beta cells. Postnatal induction of ERRgamma 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 beta cell-specific ERRgamma expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge. Notably, forced expression of ERRgamma in iPSC-derived beta-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 beta cell-deficient mice. These results identify a key role for ERRgamma in beta cell metabolic maturation, and offer a reproducible, quantifiable, and scalable approach for in vitro generation of functional human beta cell therapeutics.