The role of diet and exercise in the transgenerational epigenetic landscape of T2DM

Journal name:
Nature Reviews Endocrinology
Year published:
Published online


Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell division. Epigenetic modifications can arise from a variety of environmental exposures including undernutrition, obesity, physical activity, stress and toxins. Transient epigenetic changes across the entire genome can influence metabolic outcomes and might or might not be heritable. These modifications direct and maintain the cell-type specific gene expression state. Transient epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors. A detailed understanding of the epigenetic signatures of insulin resistance and the adaptive response to exercise might identify new therapeutic targets that can be further developed to improve insulin sensitivity and prevent obesity. This Review focuses on the current understanding of mechanisms by which lifestyle factors affect the epigenetic landscape in type 2 diabetes mellitus and obesity. Evidence from the past few years about the potential mechanisms by which diet and exercise affect the epigenome over several generations is discussed.

At a glance


  1. The main forms of epigenetic modifications.
    Figure 1: The main forms of epigenetic modifications.

    Several types of epigenetic modifications have been identified. (1) Modification of nucleosides in DNA such as by methylation and hydroxymethylation. (2) Post-translational modification of histone proteins by methylation, acetylation, ubiquitylation, SUMOylation, citrullination and ADP-ribosylation. (3) Changes in small noncoding RNA expression. Nucleoside and histone modifications regulate gene transcription by modulating the conformation of the chromatin and the access of DNA binding factors. Small noncoding RNAs (such as microRNAs) regulate gene expression by prompting mRNA degradation or modulating protein translation.

  2. Putative effects of exercise and obesity on the predisposition to metabolic diseases.
    Figure 2: Putative effects of exercise and obesity on the predisposition to metabolic diseases.

    a | In response to exercise or diet, the epigenome of gametes (depicted here for spermatozoa) is remodelled. b | After fertilization, these epigenetic changes will affect the developmental programming of the embryo. In utero, the developing embryo is susceptible to other environmental influences from the mother that can potentiate or suppress signals from the gametes. c | Exercise might influence the spermatozoan epigenome and enable transmission of epigenetic information to affect the development of the central nervous system and brain processes such as feeding behaviour. This process could lead to positive metabolic outcomes. Alternatively, according to the thrifty phenotype hypothesis, if exercise triggers an epigenetic response that is similar to caloric restriction of the gamete, the offspring might have a predisposition for metabolic disease when faced with a state of food abundance due to an increased fat storage capacity. Obese fathers could transmit epigenetic markers on genes that regulate brain development and appetite control, thereby predisposing their offspring to obesity. d | Epigenetic inheritance might be propagated to successive generations by so-called transgenerational epigenetic inheritance.

  3. Potential effect of environmentally induced epigenetic changes on gene expression.
    Figure 3: Potential effect of environmentally induced epigenetic changes on gene expression.

    In this hypothetical model, gene A is hypomethylated, while gene B is hypermethylated in response to environmental cues. Gene expression changes might not occur until a secondary environmental stress, or specific physiological state is altered, thereby enabling specific transcription factors to bind to the hypomethylated gene A, but not to hypermethylated gene B, which results in transcription of gene A. This model also explains the often observed discrepancy between DNA methylation and transcriptional changes. In this model, the same epigenetic modification in multiple tissues might only be functionally relevant in a given tissue if a specific transcription factor is also activated.


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  1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark.

    • Romain Barrès &
    • Juleen R. Zierath
  2. Department of Molecular Medicine and Department of Physiology and Pharmacology, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, SE 171 77 Stockholm, Sweden.

    • Juleen R. Zierath


Both authors researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the article before submission.

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  • Romain Barrès

    Romain Barrès is Associate Professor at the Novo Nordisk Center for Basic Metabolic Research at the University of Copenhagen, Denmark. His research focuses on mechanisms by which environmental factors induce epigenetic modifications, thus predisposing or protecting from diabetes mellitus.

  • Juleen R. Zierath

    Juleen R. Zierath is a Professor at the Karolinska Institutet, Sweden, and the Novo Nordisk Center for Basic Metabolic Research at the University of Copenhagen, Denmark. Her research focuses on the pathogenesis of type 2 diabetes mellitus and the adaptive response of skeletal muscle to exercise.

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