第 1257 回 Energy metabolic transition towards the functional beta cells演者： Eiji Yoshihara, Ph. D. (Staff Scientist, The Salk Institute, Ron Evans Lab )
場所： 京都大学ウイルス再生研２号館（旧ウイルス研本館）１階 セミナー室
In healthy individuals, pancreatic islet β cells secrete insulin in response to nutrients such as glucose, amino acids and free fatty acids to regulate whole body glucose and lipid metabolism, while β cell failure or impaired function is tightly associated with development both type 1 and type 2 diabetes. Human cadarveric islets transplantation has been shown that the most effective therapeutics for end stage of diabetes, while the shortage of human islets limit the chance for treating diabetes for patients. Therefore the continuing challenges in treating diabetes placed the development of transplantable functional β cells as one of the central goals of the field. Previously, it has shown that the possibility to generate insulin producing human beta like cells from human Pluripotent Stem Cells, but those cells generated in vitro has basically lack the robust glucose responsiveness. So the challenges remain in identifying the pathway triggering robust glucose responsiveness in β cells for generating functional human beta cells. Pancreatic β cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify orphan nuclear receptor, 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, with enhancing maximum oxidative capacity. Moreover, these cells rapidly rescue diabetes when transplanted into Type1 diabetic mice. These results identify a key role for ERRγ in β cell maturation, and highlight the importance of metabolic regulation for generating functional β cells.
連絡先：生命システム研究部門 発がん機構分野 増谷 弘 (TEL:751−4026）