Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice
| Autor: | Millership, SJ, Tunster, SJ, Van de Pette, M, Choudhury, AI, Irvine, EE, Christian, M, Fisher, AG, John, RM, Scott, J, Withers, DJ |
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| Přispěvatelé: | Wellcome Trust, Medical Research Council, Tunster, Simon [0000-0002-2242-9452], Van De Pette, Mathew [0000-0002-1423-5957], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
EXPRESSION
lcsh:Internal medicine Imprinted genes Neuronatin FEEDING-BEHAVIOR OVERGROWTH PROTEIN PEG paternally expressed gene Nerve Tissue Proteins METABOLISM DEVELOPMENTAL ORIGINS GLUCOSE Genomic Imprinting Mice Endocrinology & Metabolism HFD high fat diet Animals Obesity lcsh:RC31-1245 CLAMS comprehensive lab animal monitoring system Growth Disorders Adiposity Postnatal growth Science & Technology SPC signal peptidase complex Body Weight Membrane Proteins WAT white adipose tissue Genetic background BODY-MASS QP GH growth hormone BAT brown adipose tissue Mice Inbred C57BL Original Article Energy homeostasis XL-ALPHA-S Energy Metabolism Life Sciences & Biomedicine Gene Deletion RC |
| Zdroj: | Molecular Metabolism, Vol 18, Iss, Pp 97-106 (2018) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Imprinted 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. Methods To 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. Results Here 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. Conclusions The 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 • Deletion of the imprinted gene neuronatin in mice alters postnatal growth. • This postnatal growth defect and subsequent catch up growth is background-specific. • Leads to reduced energy expenditure, hyperphagia and leptin resistance in adulthood. • Nnat null mice are more susceptible to obesity via aging or high fat diet feeding. • Defects in normal insulin and growth hormone secretion may underpin these findings. |
| Databáze: | OpenAIRE |
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