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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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 3

Notch activation leads to loss of MafA in mouse and human β cells.

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Notch activation leads to loss of MafA in mouse and human β cells. (A) R...
(A) Representative images of pancreatic sections from β-NICD and Cre– control mice, stained with antibodies directed against insulin and MafA (n = 6 mice/group, quantification shown in Supplemental Figure 3C). (B) Western blots in islets isolated from β-NICD and Cre– control mice. (C) Representative images of immunofluorescence of fixed MIN6-rTTA3 cells transfected with doxycycline-inducible NICD-HA (or GFP control) after stimulation with doxycycline for 24 hours, with quantitation of percentage of NICD+ cells with detectable MafA, Pdx1, or Nkx6.1 (n = 3 biologic replicates). Boxed region in second row is shown amplified; arrowheads indicate Notch+ cells with absent MafA.(D) MafA and insulin staining in dispersed human β cells transduced with lentivirus expressing GFP or NICD. Representative images from 3 individual donors selected out of a total sample size of 6 donors. (E) GSIS in islets from healthy human donors transduced with lentivirus expressing GFP or NICD. Results are expressed as fold increase in insulin secretion (16.8 mM glucose/2.8 mM glucose) and reflect data from 5 individual donors. **P < 0.01, ratio paired t test. (F) Western blots from MIN6-rTTA3 cells with stable integration of doxycycline-dependent N1ΔE-myc (or luciferase control) after stimulation with doxycycline for 24 hours. Doxy, doxycycline. (G) Western blots from MIN6-rTTA3 cells with stable integration of doxycycline-dependent N1ΔE-myc after stimulation with doxycycline for the indicated amount of time. (H) Mafa expression in MIN6-rTTA3 cells with stable integration of doxycycline-dependent N1ΔE-myc (or luciferase control) after stimulation with doxycycline for 24 hours (n = 3 biologic replicates). Scale bars: 20 μm. All data are shown with group means.