Epigenetics in Human Obesity and Type 2 Diabetes

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Abstract

Epigenetic mechanisms control gene activity and the development of an organism. The epigenome includes DNA methylation, histone modifications, and RNA-mediated processes, and disruption of this balance may cause several pathologies and contribute to obesity and type 2 diabetes (T2D). This Review summarizes epigenetic signatures obtained from human tissues of relevance for metabolism—i.e., adipose tissue, skeletal muscle, pancreatic islets, liver, and blood—in relation to obesity and T2D. Although this research field is still young, these comprehensive data support not only a role for epigenetics in disease development, but also epigenetic alterations as a response to disease. Genetic predisposition, as well as aging, contribute to epigenetic variability, and several environmental factors, including exercise and diet, further interact with the human epigenome. The reversible nature of epigenetic modifications holds promise for future therapeutic strategies in obesity and T2D.

Abstract

Epigenetic factors are suggested to contribute to metabolic dysfunctions. In this Review, Ling and Rönn summarize evidence for altered DNA methylation, both as a cause and a consequence of human obesity and type 2 diabetes. As epigenetic alterations are dynamic in nature, they may also provide targets for drug development.

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Most cited references 89

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Editing DNA Methylation in the Mammalian Genome.

X. Shawn Liu, Hao Wu, Xiong Ji … (2016)

Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.

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Epigenetic inheritance at the agouti locus in the mouse.

H. D. Morgan, H. Sutherland, D I Martin … (1999)

Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germ line in mammals, so that only genetic traits are inherited. Here we describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow ( A(vy)/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene (A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Avy mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an A(vy) dam has the agouti phenotype, her offspring are more likely to be agouti. We demonstrate here that this maternal epigenetic effect is not the result of a maternally contributed environment. Rather, our data show that it results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modification. Because retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.

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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Robert Scott, Laura J. Scott, Reedik Mägi … (2017)

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

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Author and article information

Contributors

Charlotte Ling

Journal

Journal ID (nlm-ta): Cell Metab

Journal ID (iso-abbrev): Cell Metab

Title: Cell Metabolism

Publisher: Cell Press

ISSN (Print): 1550-4131

ISSN (Electronic): 1932-7420

Publication date PMC-release: 07 May 2019

Publication date (Print): 07 May 2019

Volume: 29

Issue: 5

Pages: 1028-1044

Affiliations

[1 ]Epigenetics and Diabetes Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden

Author notes

[∗ ]Corresponding author charlotte.ling@ 123456med.lu.se

Article

Publisher ID: S1550-4131(19)30137-8

DOI: 10.1016/j.cmet.2019.03.009

PMC ID: 6509280

PubMed ID: 30982733

SO-VID: 2ba79b78-5fb7-489c-9ed8-99e9f3d3802e

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Epigenetics in Human Obesity and Type 2 Diabetes

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Most cited references 89

Editing DNA Methylation in the Mammalian Genome.

Epigenetic inheritance at the agouti locus in the mouse.

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

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