Imprinted Genes, Postnatal Adaptations and Enduring Effects on Energy Homeostasis

Frontera, Margalida; Dickins, Benjamin; Plagge, Antonius; Kelsey, Gavin

doi:10.1007/978-0-387-77576-0_4

Cited by 34 publications

(34 citation statements)

References 132 publications

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“…Epigenetic factors, defined as the changes in gene function that do not relate to changes in DNA sequence, begin in utero (or in some cases in previous generations) and also contribute. 9 Infants of diabetic mothers and of mothers who smoke during pregnancy have increased risk of subsequent obesity. Infant feeding practices may also play a role, particularly a shortened period of breast-feeding.…”

Section: A Pathophysiology Of Obesitymentioning

confidence: 99%

American Heart Association Childhood Obesity Research Summit Report

Daniels

Jacobson²,

McCrindle³

et al. 2009

Circulation

101

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Section: A Pathophysiology Of Obesitymentioning

confidence: 99%

American Heart Association Childhood Obesity Research Summit Report

Daniels

Jacobson²,

McCrindle³

et al. 2009

Circulation

101

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“…Besides the Gnas locus, mouse studies have shown that altered expression of genes in five other imprinted clusters results in adult obesity (reviewed in Frontera et al 21 ). Thus, obesity is associated with overexpression of the paternally expressed Peg1/Mest gene, with the loss of paternal expression of Peg3, Igf2 and Dlk/Pref1, and with the loss of maternal expression of Atp10c.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

et al. 2009

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Objective: The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein a-subunit, Gsa, its isoform XLas and their variant truncated neural forms GsaN1 and XLN1. Gsa and GsaN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLas and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsa and XLas, and truncated forms GsaN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsaN1 and XLN1, but affects full-length Gsa and XLas, allowing us to address the role of full-length Gsa and XLas. The aim of this study was therefore to determine the metabolic phenotypes of Oed and Sml mice, and to correlate phenotypes with affected transcripts. Methods: Mice were fed standard or high-fat diets and weighed regularly. Fat mass was determined by DEXA analysis. Indirect calorimetry was used to measure metabolic rate. Glucose was measured in tolerance tests and biochemical parameters in fasted plasma samples. Histological analysis of fat and liver was carried out post mortem. Results: Oed mice are obese on either diet and have a reduced metabolic rate. Sml mice are lean and are resistant to a high-fat diet and have an increased metabolic rate. Conclusion: Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsa. In contrast, on paternal inheritance, Sml mice were small and resistant to the development of obesity on a high-fat diet, effects that can be attributed to mutant XLas. Thus, the neural isoforms, GsaN1 and XLN1, do not appear to play a role in these metabolic phenotypes.

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“…The findings that mouse knockouts for several imprinted genes have disturbed metabolic control highlights the hypothalamus as a potential major site for the action of imprinted genes (Charalambous et al 2007, Frontera et al 2008. The hypothalamus is a key regulator of many endocrine functions and is involved in the regulation of energy balance through its influence on food intake, metabolic rate and body temperature by the action of a dozen small nuclei.…”

Section: The Hypothalamus As a Hotspot Of Imprinted Gene Expressionmentioning

confidence: 99%

“…Paternal genes can be considered resource demanding, whilst maternal genes in offspring have an interest in conserving maternal resources for the future reproductive health of the mother (Moore & Haig 1991). Most imprinted genes that influence foetal and early postnatal growth and development satisfy the predictions of conflict theory, but the theory has had less success in predicting the actions of imprinted genes in adults, and there seems to be no neat division between the effects of maternally and paternally expressed genes in processes such as metabolism (Haig 2004, Frontera et al 2008.…”

Section: Reasons For Imprinting In the Hypothalamusmentioning

confidence: 99%

Imprinted genes and hypothalamic function

Ivanova

Kelsey

2011

Journal of Molecular Endocrinology

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Genomic imprinting is an important and enigmatic form of gene regulation in mammals in which one copy of a gene is silenced in a manner determined by its parental history. Imprinted genes range from those with constitutive monoallelic silencing to those, typically more remote from imprinting control regions, that display developmentally regulated, tissuespecific or partial monoallelic expression. This diversity may make these genes, and the processes they control, more or less sensitive to factors that modify or disrupt epigenetic marks. Imprinted genes have important functions in development and physiology, including major endocrine/neuroendocrine axes. Owing to is central role in coordinating growth, metabolism and reproduction, as well as evidence from genetic and knockout studies, the hypothalamus may be a focus for imprinted gene action. Are there unifying principles that explain why a gene should be imprinted? Conflict between parental genomes over limiting maternal resources, but also co-adaptation between mothers and offspring, have been invoked to explain the evolution of imprinting. Recent reports suggest there may be many more genes imprinted in the hypothalamus than hitherto expected, and it will be important for these new candidates to be validated and to determine whether they conform to current notions of how imprinting is regulated. In fully evaluating the role of imprinted genes in the hypothalamus, much work needs to be done to identify the specific neuronal populations in which particular genes are expressed, establish whether there are pathways in common and whether imprinted genes are involved in long-term programming of hypothalamic functions.

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Imprinted Genes, Postnatal Adaptations and Enduring Effects on Energy Homeostasis

Cited by 34 publications

References 132 publications

American Heart Association Childhood Obesity Research Summit Report

American Heart Association Childhood Obesity Research Summit Report

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

Imprinted genes and hypothalamic function

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