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Having a high-fat diet (HFD) is not only linked to obesity but also to an increased risk of developing heart disease, type 2 diabetes, and certain mental health disorders. With obesity levels on the rise, it’s critical that we know more about how a HFD affects the body and find ways for early prevention. In recent years, there has been a growing area of interest into the behavioral consequences of a HFD and if these are passed onto subsequent generations through epigenetics.
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With various areas of health research that looks for associations across generations, the discussion often turns to the epigenetic phenomenon of transgenerational inheritance. Emerging evidence suggests that epigenetic marks are linked to the transgenerational inheritance of the effects of toxins and stress, with little research in the area of overnutrition. Nutrition has already been suggested to have an epigenetic impact on puberty in girls and specifically, overnutrition might contribute towards the development of diabetes through epigenetic marks. But does this happen across multiple generations?

This question is similar to what a recent collaboration between ETZ Zurich and the Babraham Institute attempted to answer1, contributing to the knowledge of complex interactions of genetic and environmental factors that cause obesity.

The term epigenetic here refers to marks that are involved in potentially altering heritable gene activity states that are not dependent on changes in DNA sequence2. As such, they can include but are not exclusive to DNA methylationhistone modificationsnon-coding RNA, and the structure of chromatin.
The HFD is already implicated with an increase in appetite, altering reward circuits, and increasing sensitivity to drugs of abuse in mice. Furthermore, Dunn et al.3 has previously demonstrated that a HFD can result in increased body weight in third generation mice (F3) – though this is only seen through the paternal lineage (the father’s children).

Gitalee Sarker, first author of the current study, and colleagues decided to probe this result further. They investigated the transmission of hedonic behaviors, metabolic phenotypes, and the sperm DNA methylome in subsequent generations of mice exposed to a HFD – producing interesting results for the transgenerational epigenetic field and influencing what direction it will go in the future.

The bulk of the results focused on male and female mice in second (F2) and third (F3) generations of lineages that were maternally exposed to a HFD diet or were not (control), with the F3 generation representing the true transgenerational effect.

The researchers demonstrated that the HFD F3 generation of female mice was more likely to consume alcohol, amphetamines, and cocaine than the control group. More interestingly, this phenomenon seemed to be only present in the F3 generation of female mice and not in their male counterparts. Such behaviors correlated with an increase in expression of delta FosB, a gene associated with addiction, in the F3 generation. However, it was unclear if such expression was specific to male or female mice in the data presented.
HFD F3 generation male mice, in contrast, were more likely to have increased body weight, fat distribution, sensitivity to insulin, and higher levels of insulin and cholesterol when compared to the control group. This, however, was not observed in F3 generation female mice. Such results suggest that there may be differential sex-specific phenotypes of F3 generation mice whose lineages/ancestors were exposed to a HFD.

In search of a potential mechanism, the research team interrogated the results epigenetically. They specifically focused on differentially methylated regions (DMRs) where DNA methylation, which is associated with gene silencing, differed between the control and HFD mice. While there were over 500 DMRs in the F1 and the F2 generation, only 6 of these overlapped between the two generations – suggesting that DNA methylation might not be implicated in the HFD transgenerational effect observed.

Another potential epigenetic mechanism mentioned by researchers was sperm small noncoding RNAs (sncRNA), as these regulate chromatin remodeling, DNA methylation, histone modifications and are essential for the development of germ cells.
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The researchers noted, “Recent studies have reported a mechanistic link between altered sperm sncRNAs and the transmission of metabolic and behavioral phenotypes in the progeny following parental stress15 or HFD exposure. It will therefore be of great interest to examine in future studies the role of sperm sncRNAs in transgenerational transmission of altered metabolic and addictive-like phenotypes in transgenerational models of maternal HFD insult.”

Overall, this study suggests that there are sex-specific inheritance phenotypes in the F3 generation which are not wholly dependent on DNA methylation. While DNA methylation could be implicated, further research may need to focus on specific DMRs. As Holland et al’s study performed, suggesting that an obesogenic diet can increase the DNA methylation of a specific rDNA variant in the subsequent generation4. Perhaps such an effect could be observed across generations in those with a HFD diet.

It’s expected that more research will come in the next few years that will piece together the contrasting and sometimes confusing findings we have regarding transgenerational inheritance.

James Cain

  1. Sarker, G. et al. Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition. Transl. Psychiatry 8, 195 (2018).
  1. Bird, A. Perceptions of epigenetics. Nature 447, 396 (2007).
  1. Dunn, G. A. & Bale, T. L. Maternal High-Fat Diet Effects on Third-Generation Female Body Size via the Paternal Lineage. Endocrinology 152, 2228–2236 (2011).
  1. Holland, M. L. et al. Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science (80-. ). 353, 495 LP-498 (2016).

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