Notch signaling dynamically regulates adult β cell proliferation and maturity
Alberto Bartolome, … , Lori Sussel, Utpal B. Pajvani
Alberto Bartolome, … , Lori Sussel, Utpal B. Pajvani
Published December 3, 2018; First published October 30, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI98098.
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Categories: Research Article Endocrinology Metabolism

Notch signaling dynamically regulates adult β cell proliferation and maturity

Abstract

Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell–specific–deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell–specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.

Authors

Alberto Bartolome, Changyu Zhu, Lori Sussel, Utpal B. Pajvani

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Figure 1

Increased Notch activity with β cell stress.

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Increased Notch activity with β cell stress. (A) Representative image of...
(A) Representative image of pancreatic sections from WT mice stained with antibodies directed against insulin and Rbpj. (B) Representative image of pancreatic sections from TNR mice. (C) Quantitation of percentage of GFP+ cells in remaining β cells from TNR mice after low-dose STZ (n = 5–9 mice/group). (D) Representative images of pancreatic sections stained with antibodies directed against Hes1 and insulin in vehicle (control) and STZ-treated TNR mice (n = 5–9 mice/group). (E) Western blots from islets isolated from TNR mice, incubated for 15 hours in medium containing indicated glucose concentrations. Representative blots from 2 experiments. (F) Gene expression in islets isolated from WT mice, cultured overnight in medium containing low (1 mM) or high (25 mM) glucose (n = 3 biologic replicates). (G) Gene expression in islets isolated from 24-week HFD-fed WT mice, as compared with normal chow diet–fed littermate controls (n = 5 mice/group). (H) Representative images of pancreatic sections stained with antibodies directed against Hes1 and insulin, with quantitation of nuclear Hes1 fluorescence intensity in β cells (n = 4–5 mice/group). Scale bars: 20 μm. All data are shown with group means. *P < 0.05; ***P < 0.001, 2-tailed t test.