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Neuronatin regulates pancreatic β cell insulin content and secretion

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., Kerr-Conte, Julie, Pattou, Francois, Ferrer, Jorge, Christian, Mark, John, Rosalind M., Latreille, Mathieu, Liu, Ming, Rutter, Guy A., Scott, James and Withers, Dominic J. 2018. Neuronatin regulates pancreatic β cell insulin content and secretion. Journal of Clinical Investigation 128 (8) , pp. 3369-3381. 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: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of First Compliant Deposit: 21 August 2018
Date of Acceptance: 17 May 2018
Last Modified: 22 Oct 2018 12:50
URI: http://orca.cf.ac.uk/id/eprint/114274

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