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      Intrauterine programming of obesity and type 2 diabetes

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          Abstract

          The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes.

          Electronic supplementary material

          The online version of this article (10.1007/s00125-019-4951-9) contains a slideset of the figures for download, which is available to authorised users.

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          Role of TET enzymes in DNA methylation, development, and cancer

          Ten eleven translocation (TET) genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to the onset and maintenance of these malignancies is largely unknown. In this review, Rasmussen and Helin highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.
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            Histone core modifications regulating nucleosome structure and dynamics.

            Post-translational modifications of histones regulate all DNA-templated processes, including replication, transcription and repair. These modifications function as platforms for the recruitment of specific effector proteins, such as transcriptional regulators or chromatin remodellers. Recent data suggest that histone modifications also have a direct effect on nucleosomal architecture. Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone-histone and histone-DNA interactions, as well as the binding of histones to chaperones.
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              Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

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                Author and article information

                Contributors
                seo10@cam.ac.uk
                Richard.saffery@mcri.edu.au
                Journal
                Diabetologia
                Diabetologia
                Diabetologia
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0012-186X
                1432-0428
                27 August 2019
                27 August 2019
                2019
                : 62
                : 10
                : 1789-1801
                Affiliations
                [1 ]ISNI 0000000121885934, GRID grid.5335.0, Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, , University of Cambridge, ; Addenbrooke’s Hospital, Level 4, Box 289, Addenbrooke’s Treatment Centre, Cambridge, CB2 0QQ UK
                [2 ]GRID grid.475435.4, Department of Endocrinology, the Diabetes and Bone-metabolic Research Unit, , Rigshospitalet, ; Copenhagen, Denmark
                [3 ]GRID grid.475435.4, Department of Obstetrics, Center for Pregnant Women with Diabetes, , Rigshospitalet, ; Copenhagen, Denmark
                [4 ]ISNI 0000 0004 0614 0346, GRID grid.416107.5, Murdoch Children’s Research Institute, , Royal Children’s Hospital, ; Flemington Road, Parkville, VIC 3052 Australia
                Article
                4951
                10.1007/s00125-019-4951-9
                6731191
                31451874
                f1f68f98-45a7-483a-9bb9-d9e62a0a6237
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 April 2019
                : 5 June 2019
                Funding
                Funded by: University of Cambridge
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Endocrinology & Diabetes
                developmental programming,epigenetic variation,intrauterine programming,life course development,maternal exposures,micrornas,obesity,paternal exposures,review,type 2 diabetes

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