Neuronatin regulates pancreatic β cell insulin content and secretion

• DOI: 10.1172/jci120115
• Publication Date: 2018-06-04T16:00:48Z
• Authors: Steven J. Millership; Gabriela Da Silva...; 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
• Keywords: 0301 basic medicine; 570; [SDV]Life Sciences [q-bio]; Immunology; ENDOPLASMIC-RETICULUM; PROTEIN; Mice, Transgenic; Nerve Tissue Proteins; Research & Experimental Medicine; Transgenic; SACCHAROMYCES-CEREVISIAE; Mice; 03 medical and health sciences; Insulin-Secreting Cells; Insulin Secretion; Genetics; Animals; Insulin; 11 Medical and Health Sciences; GENE-EXPRESSION; Science & Technology; INS GENE; MUTATIONS; Research & Experimental; Diabetes; Beta cells; Membrane Proteins; Cell Biology; METABOLIC STATUS; QP; MICE; Glucose; Medicine, Research & Experimental; Gene Expression Regulation; Medicine; SIGNAL PEPTIDASE COMPLEX; MEMBRANE TOPOLOGY; Life Sciences & Biomedicine; RC; Research Article

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.