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Neuropeptide Y expression marks partially differentiated β cells in mice and humans
Pope Rodnoi, … , Alexandra E. Butler, Sangeeta Dhawan
Pope Rodnoi, … , Alexandra E. Butler, Sangeeta Dhawan
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e94005. https://doi.org/10.1172/jci.insight.94005.
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Research Article Development Endocrinology

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

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Abstract

β Cells are formed in embryonic life by differentiation of endocrine progenitors and expand by replication during neonatal life, followed by transition into functional maturity. In this study, we addressed the potential contribution of neuropeptide Y (NPY) in pancreatic β cell development and maturation. We show that NPY expression is restricted from the progenitor populations during pancreatic development and marks functionally immature β cells in fetal and neonatal mice and humans. NPY expression is epigenetically downregulated in β cells upon maturation. Neonatal β cells that express NPY are more replicative, and knockdown of NPY expression in neonatal mouse islets reduces replication and enhances insulin secretion in response to high glucose. These data show that NPY expression likely promotes replication and contributes to impaired glucose responsiveness in neonatal β cells. We show that NPY expression reemerges in β cells in mice fed with high-fat diet as well as in diabetes in mice and humans, establishing a potential new mechanism to explain impaired β cell maturity in diabetes. Together, these studies highlight the contribution of NPY in the regulation of β cell differentiation and have potential applications for β cell supplementation for diabetes therapy.

Authors

Pope Rodnoi, Mohan Rajkumar, Abu Saleh Md Moin, Senta K. Georgia, Alexandra E. Butler, Sangeeta Dhawan

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Figure 1

NPY marks nascent β cells and is restricted from pancreatic and endocrine progenitors.

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NPY marks nascent β cells and is restricted from pancreatic and endocrin...
(A) Immunostaining of a representative pancreatic section from wild-type mouse embryos at E12.5 showing immunostaining for pancreatic progenitor marker Pdx1 and neuropeptide Y (NPY) or the same section overlaid with glucagon (Pdx1: cyan; NPY: red; glucagon: green), showing exclusion of NPY from pancreatic progenitors. (B) Immunostaining of representative pancreatic sections from Ngn3-EGFP (EGFP expression driven by Neurogenin3 promoter to mark endocrine progenitors) embryos at E15.5, showing NPY (red), GFP (green), insulin (Ins; cyan) and overlay with DAPI (to counterstain the nuclei; blue). Arrows indicate cells with high GFP expression defining endocrine progenitors. (C) Immunostaining for NPY (red), glucagon (Glu; green), and insulin (cyan), with DAPI (blue) in fetal mouse (E17.5) and human (16 weeks pc/gestation) pancreatic sections. Larger arrows mark overlap of NPY with insulin, while smaller arrows mark overlap of NPY with glucagon. Scale bar: 50 μm. For A and B and mouse data in C, n = 4 animals.

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