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Neuronatin regulates pancreatic β cell insulin content and secretion
Steven J. Millership, … , James Scott, Dominic J. Withers
Steven J. Millership, … , James Scott, Dominic J. Withers
Published June 4, 2018
Citation Information: J Clin Invest. 2018;128(8):3369-3381. https://doi.org/10.1172/JCI120115.
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Research Article Cell biology Genetics Article has an altmetric score of 27

Neuronatin regulates pancreatic β cell insulin content and secretion

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Abstract

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone- and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat-null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole-animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.

Authors

Steven J. Millership, Gabriela Da Silva Xavier, Agharul I. Choudhury, Sergio Bertazzo, Pauline Chabosseau, Silvia M.A. Pedroni, Elaine E. Irvine, Alex Montoya, Peter Faull, William R. Taylor, Julie Kerr-Conte, Francois Pattou, Jorge Ferrer, Mark Christian, Rosalind M. John, Mathieu Latreille, Ming Liu, Guy A. Rutter, James Scott, Dominic J. Withers

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Figure 1

Effect of Nnat deficiency in vivo.

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Effect of Nnat deficiency in vivo.
(A) Targeted inactivation of the Nnat...
(A) Targeted inactivation of the Nnat gene. Exon 1 was flanked by loxP sites with the neomycin selection cassette (Neo) flanked by FRT sites, to produce a floxed and null allele. (B and C) Quantitative RT-PCR and representative Western blot analysis of Nnat expression in tissues of WT, heterozygous Nnat+/–m (maternal deletion), heterozygous Nnat+/–p (paternal deletion), and homozygous Nnat–/– mice on C57BL/6J background. Data are compared with WT mice (n = 4–7 animals per group, Kruskal-Wallis or Mann-Whitney U test). (D) Measurement of insulin secretion in vivo in response to i.p. glucose in 10-week-old male βcellKO-Nnat+/–p versus control mice on C57BL/6J background (n = 8 animals per genotype, ANOVA with repeated measures). Inset shows box-and-whisker plot of the same data plotted as percentage insulin secretion across all time points compared with basal insulin values (at T = 0). (“‡” indicates statistically significant increases, P < 0.05, in secretion in WT mice compared with basal insulin values.) (E) Fasted (4-hour) blood glucose levels from 10-week-old chow-fed male βcellKO-Nnat+/–p versus control mice and from male mice of both genotypes fed Western diet for 4 weeks (14 weeks old) and 12 weeks (22 weeks old) (Student’s t test for each time point, all C57BL/6J, n = 7–14 animals per genotype, per time point, minimum 2 independent cohorts). (F and G) Glucose tolerance in overnight-fasted Western diet–fed groups as in E (ANOVA with repeated measures). Insets show means of area under the curve (AUC) for both genotypes at both time points (Student’s t test for each). (*P < 0.05, **P < 0.01).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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