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

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 6

Regulation of NNAT expression in islets by glucose and diet.

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Regulation of NNAT expression in islets by glucose and diet. (A) Quantit...
(A) Quantitative RT-PCR analysis of Nnat mRNA in isolated islets from 10-week-old male WT C57BL/6J mice cultured in low-glucose (3 mM) or high-glucose (16.7 mM) conditions for 6 hours. Hprt mRNA was used as an internal control, and data are compared with 3-mM cultures (n = 5 animals per group, Mann-Whitney U test). (B) Parallel islet preparations receiving the same treatment as in A were analyzed for protein expression by Western blotting. β-Tubulin was used as a loading control. (C) Representative Western blot analysis of NNAT protein expression in isolated pancreatic islets of 10-week-old male WT C57BL/6J mice that were chow-fed (Fed), fasted overnight (Fasted), or fed high-fat diet for 72 hours (HFD). Similar experiments were also performed with 72-hour feeding with Western diet (Western) compared with chow-fed controls (Chow). β-Tubulin was used as a loading control (n = 5 animals per group, Kruskal-Wallis for HFD studies, left panels, and Mann-Whitney U test for Western diet studies, right panels). Mean values for each condition are shown below each panel, compared with chow-fed controls. (*P < 0.05, **P < 0.01).