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Neuronatin regulates pancreatic β cell insulin content and secretion

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Millership, Steven J., da Silva Xavier, Gabriela, Choudhury, Agharul I., Bertazzo, Sergio, Chabosseau, Pauline, Pedroni, Silvia M. A., Irvine, Elaine E., Montoya, Alex, Faull, Peter, Taylor, William R. et al.
(2018) Neuronatin regulates pancreatic β cell insulin content and secretion. Journal of Clinical Investigation . doi:10.1172/JCI120115

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Official URL: http://dx.doi.org/10.1172/JCI120115

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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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Pancreatic beta cells, Obesity -- Physiological aspects
Journal or Publication Title: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
ISSN: 1558-8238
Official Date: 4 June 2018
Dates:
DateEvent
4 June 2018Available
18 May 2018Accepted
DOI: 10.1172/JCI120115
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
093082/Z/10/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
098565/Z/12/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
MC-A654-5QB40[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
WT098424AIAWellcome Trusthttp://dx.doi.org/10.13039/100010269
BDA/11/0004210Diabetes UKhttp://dx.doi.org/10.13039/501100000361
BDA/15/0005275Diabetes UKhttp://dx.doi.org/10.13039/501100000361
MR/J0003042/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/L020149/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/N00275X/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIED[RS] Royal Societyhttp://dx.doi.org/10.13039/501100000288
BDA/13/0004672Diabetes UKhttp://dx.doi.org/10.13039/501100000361
FC001179Francis Crick Institutehttp://dx.doi.org/10.13039/100010438
81070629[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81620108004 [NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81370895[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
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