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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 4

NNAT interaction with the SPC and modulation of preproinsulin handling.

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NNAT interaction with the SPC and modulation of preproinsulin handling.
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(A) Overview of affinity purification/mass spectrometry (AP/MS) screen for novel interaction partners of NNAT. Endogenous NNAT was immunoprecipitated (IP) from MIN6 cell lysates and interacting partners in co-IPs analyzed by liquid chromatography/mass spectrometry (LC/MS). (B) Heatmap from AP/MS analysis of top protein hits in IPs using antibodies against NNAT (NNAT Ab) and control IPs with rabbit immunoglobulins (IgG). Relatively high abundance is shown in yellow and relatively low abundance in blue. (C) Lysates from HEK293T cells expressing c-Myc–tagged SEC11A and FLAG-tagged NNAT were immunoprecipitated using anti–c-Myc antibodies. Proteins in input and IP samples were detected by Western blotting using anti–c-Myc and anti-FLAG antibodies. Panel shows a representative blot of 3 independent experiments. (D) INS1E cells transiently transfected with siRNA targeting Nnat or Sec11a were assayed in vitro for GSIS at low (3 mM) and high (25 mM) glucose. A scramble siRNA served as a control with data expressed as mean insulin secretion per unit cellular protein. Graph on the right shows total insulin content in cell lysates. (n = 9 independent cultures per group, 3 independent experiments, 2-way ANOVA [left graph] and 1-way ANOVA [right graph].) (E) INS1E cells transfected with c-Myc–tagged preproinsulin and siRNAs targeting Nnat or Sec11a were pulse-labeled with 35S-Cys/Met. Lysates immunoprecipitated with anti–c-Myc agarose were analyzed by autoradiography. Associated bar chart shows preproinsulin and proinsulin band intensities in multiple experiments quantified by densitometry and expressed as percentage processing of preproinsulin (n = 3 cultures per group from 3 independent experiments, 1-way ANOVA). (F) Similar experiments performed as in E, from 3-hour chase cell lysates (C) and media (M), quantified as in E (n = 4 cultures per group from 3 independent experiments, 1-way ANOVA for both C and M). (*P < 0.05, **P < 0.01).

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

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