Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877818308044 |
| _version_ | 1818387030524035072 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Steven J. Millership |
| collection | DOAJ |
| description | 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. Keywords: Obesity, Postnatal growth, Imprinted genes, Neuronatin, Genetic background, Energy homeostasis |
| first_indexed | 2024-12-14T04:03:28Z |
| format | Article |
| id | doaj.art-26d4b09f14664e5591a179872fcd1a07 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T04:03:28Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-26d4b09f14664e5591a179872fcd1a072022-12-21T23:17:53ZengElsevierMolecular Metabolism2212-87782018-12-011897106Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv miceSteven J. Millership0Simon J. Tunster1Mathew Van de Pette2Agharul I. Choudhury3Elaine E. Irvine4Mark Christian5Amanda G. Fisher6Rosalind M. John7James Scott8Dominic J. Withers9MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UKSchool of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UKMRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UKMRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UKMRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UKInstitute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UKMRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UKSchool of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UKNational Heart and Lung Institute, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UKMRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK; Corresponding author. Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.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. Keywords: Obesity, Postnatal growth, Imprinted genes, Neuronatin, Genetic background, Energy homeostasishttp://www.sciencedirect.com/science/article/pii/S2212877818308044 |
| spellingShingle | 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 Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice Molecular Metabolism |
| title | Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice |
| title_full | Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice |
| title_fullStr | Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice |
| title_full_unstemmed | Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice |
| title_short | Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice |
| title_sort | neuronatin deletion causes postnatal growth restriction and adult obesity in 129s2 sv mice |
| url | http://www.sciencedirect.com/science/article/pii/S2212877818308044 |
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