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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Neuronatin regulates pancreatic β cell insulin content and secretion

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 2

Insulin content and secretion in Nnat-deficient islets.

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Insulin content and secretion in Nnat-deficient islets. (A) Insulin secr...
(A) Insulin secretion in static incubations of primary isolated islets from 10-week-old male Nnat+/–p and WT mice was determined in vitro under low-glucose (3 mM) and high-glucose (16.7 mM) conditions (n = 12 animals per group, 2-way ANOVA). (B) Insulin secretion in static incubations of primary isolated islets from 10-week-old male control and βcellKO-Nnat+/–p mice was determined as in A (n = 8 mice per genotype, both 3 independent experiments). (C and D) Mature insulin content (C) (n = 11 for WT and 8 for Nnat+/–p, Student’s t test) and proinsulin content (D) (n = 6 animals per group, Mann-Whitney U test) were quantified in isolated islets from 10-week-old male WT and Nnat+/–p mice and normalized to total protein. (E) Western blotting analysis of protein levels in primary isolated islets from 10-week-old male Nnat+/–p and WT mice. A representative blot of 2 independent experiments (n = 4 mice per genotype, Student’s t test) is shown. β-Tubulin was used as a loading control. Mean values for band intensities in multiple experiments quantified by densitometry are shown below each panel as well as in associated bar charts for insulin species, all expressed relative to WT samples (*P < 0.05, **P < 0.01, ***P < 0.001).