Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice

Steven J Millership,Simon J Tunster,Mathew Van De Pette,Agharul I Choudhury,Elaine E Irvine,Mark Christian,Amanda G Fisher,Rosalind M John,James Scott,Dominic J Withers

doi:10.1016/j.molmet.2018.09.001

Steven J Millership, Simon J Tunster + Show 8 more

Open Access

https://doi.org/10.1016/j.molmet.2018.09.001

Copy DOI

Abstract

ObjectiveImprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice. However, our recent studies of Nnat null mice on this genetic background failed to display any body weight or feeding phenotypes but revealed a defect in glucose-stimulated insulin secretion due to the ability of neuronatin to potentiate signal peptidase cleavage of preproinsulin. Nnat deficiency in beta cells therefore caused a lack of appropriate storage and secretion of mature insulin. MethodsTo further explore the potential role of Nnat in the regulation of body weight and adiposity, we studied classical imprinting-related phenotypes such as placental, fetal, and postnatal growth trajectory patterns that may impact upon subsequent adult metabolic phenotypes. ResultsHere we find that, in contrast to the lack of any body weight or feeding phenotypes on the C57BL/6J background, deletion of Nnat in mice on 129S2/Sv background causes a postnatal growth restriction with reduced adipose tissue accumulation, followed by catch up growth after weaning. This was in the absence of any effect on fetal growth or placental development. In adult 129S2/Sv mice, Nnat deletion was associated with hyperphagia, reduced energy expenditure, and partial leptin resistance. Lack of neuronatin also potentiated obesity caused by either aging or high fat diet feeding. ConclusionsThe imprinted gene Nnat plays a key role in postnatal growth, adult energy homeostasis, and the pathogenesis of obesity via catch up growth effects, but this role is dependent upon genetic background.

Highlights

Genomic imprinting results in monoallelic expression of a subset of mammalian genes specified by their parent-of-origin [1]
Highlighting the importance of imprinted gene dosage, human genetic disorders and mouse models with altered imprinted gene expression are associated with a wide range of diseases ranging from psychiatric conditions and cancer to metabolic disorders such as obesity and diabetes [17e25]
In view of the key roles of imprinted genes in placental, fetal, and early postnatal growth and their influence on metabolic phenotypes in adulthood via such roles, we undertook a series of studies to understand the role of neuronatin in these processes

Summary

Introduction

Genomic imprinting results in monoallelic expression of a subset of mammalian genes specified by their parent-of-origin [1]. Many of these w150 genes are critical for placental function and normal fetal growth and development [2e5] and in a wide range of processes vital for the survival and development of neonates including thermoregulation, feeding behavior, and regulation of glucose and lipid metabolism [6e14]. With possible multiple paternity across litters, males are related to just some of the offspring of a specific mother; it is in his genetic interest for his offspring to extract maximal maternal resources [15]. Control of growth and development by Abbreviations: WAT, white adipose tissue; BAT, brown adipose tissue; SPC, signal peptidase complex; PEG, paternally expressed gene; HFD, high fat diet; GH, growth hormone; CLAMS, comprehensive lab animal monitoring system

Methods

Results

Conclusion