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 October 30, 2018
Citation Information: J Clin Invest. 2019;129(1):268-280. https://doi.org/10.1172/JCI98098.
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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 7

Notch loss of function stabilizes β cell MafA and improves glucose tolerance.

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Notch loss of function stabilizes β cell MafA and improves glucose toler...
(A) Representative image of islet cells dispersed from WT mice transduced with lentivirus expressing DNMAML-GFP (or GFP control) and exposed to 100 nM palmitate and 25 mM glucose for 72 hours. Arrows indicate DNMAML+ cells. Quantitation shows insulin+ MafA+ islet cells in transduced vs. nontransduced cells (n = 3 independent experiments). ***P < 0.001, 1-way ANOVA and Dunnett’s multiple comparisons post hoc test. (B) Western blots and quantitation of residual MafA-Myc signal expressed as percentage of baseline from MIN6 cells with stable integration of DNMAML-GFP (or GFP control) transiently transfected with MafA-myc, then treated with 10 μg/ml cycloheximide (Chx) for the indicated times (n = 3 independent experiments). *P < 0.05; **P < 0.01, 2-tailed t test. (C) GTT in TAM-treated, HFD-fed MIP-β-DNMAML and Cre– control mice (n = 9–11 mice/group) per experimental protocol shown in Supplemental Figure 8C. *P < 0.05, 2-tailed t test. (D) Representative images and quantitation of MafA fluorescence intensity in pancreatic sections from HFD-fed MIP-β-DNMAML and Cre– control mice (n = 4 mice/group). P = 0.054, 2-tailed t test. (E) Gene expression in islets isolated from HFD-fed MIP-β-DNMAML and Cre– control mice (n = 4–5 mice/group). *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed t test. (F) GTT in HFD-fed MIP-β-Rbpj and Cre– control mice (n = 9 mice/group). *P < 0.05; **P < 0.01, 2-tailed t test. (G) Representative images and quantitation of MafA fluorescence intensity in pancreatic sections from HFD-fed MIP-β-Rbpj and Cre– control mice (n = 4 mice/group). *P < 0.05, 2-tailed t test. (H) Gene expression in islets isolated from HFD-fed MIP-β-Rbpj and Cre– control mice (n = 5–6 mice/group). *P < 0.05; **P < 0.01, 2-tailed t test. Scale bars: 20 μm. All data are shown with group means ± SEM.