Obesity and substance abuse represent two of the major public health issues of this millennium, having a deleterious impact on our morbidity, mortality and health expenditure. According to WHO in 2016, approximately 1.9 billion adults are overweight and 650 million among them are obese. In addition, according to the World Drug Report 2018, around 275 million people worldwide have been reported to have used an illicit drug at least once in 2016. Considering the financial and social burden, it is of the utmost importance that we better understand these disorders, while at the same time developing preventative and therapeutic solutions.

Both obesity and drug addiction are multifactorial disorders that reflect a complex interaction between gene and environment. While genetic factors undoubtedly play a crucial role, they alone cannot explain the recent dramatic rise of obesity or addiction. This has raised interest in understanding the potential role of epigenetics as a mediator of gene-environment interaction in the cause of these diseases.

More recently, the concept of ‘early life programming’ has gained wide attention among obesity and addiction researchers as a key enabler of epigenetic modifications. Early life programming refers to the fact that environmental insults, such as stress, during critical periods of fetal development can induce irreversible physiological changes in the form of various diseases later in life.

In the context of ‘early life programming’, many recent studies have reported that obesity or overnutrition during pregnancy and lactation has a significant impact on the development of obesity and related metabolic syndrome in offspring later in life. Similar work also shows the link between gestational exposure to illicit drugs and increased susceptibility to addiction in the offspring. However, to date, little is known about the link between maternal junk food consumption during pregnancy and lactation and the predisposition to substance abuse.

We show that 9 weeks maternal high fat diet exposure induces obesogenic, and addictive-like phenotypes … over three generations in the absence of any further high fat diet exposure.

Considering the escalating growth of obesity and drug addiction and their shared features, in our current study we focused on exploring whether maternal overnutrition in mice during perinatal periods can increase the susceptibility to addiction and obesity in the progeny. Our earlier study showed that maternal high-fat diet (HFD) in mice over a period of 9 weeks (3 weeks preconception, 3 weeks gestation and 3 weeks lactation) led to addictive-like behaviors and metabolic syndrome-like phenotypes in the first generation (F1). The addictive and metabolic phenotypes were associated with a hypodopaminergic mesolimbic reward system as a common underlying mechanism.

This observation has driven us to explore whether the observed addictive-like and obesogenic phenotypes can be transmitted across generations. And if yes, what is the underlying mechanism for such transgenerational inheritance? To be more specific, which epigenetic mark carries this information across generations?

To answer these questions, we took the male offspring (F1) born to 9 weeks HFD and chow-fed (control) dams (F0). F1 males from both groups were mated with naïve chow-fed females to generate the second generation (F2) offspring. Similarly, F2 male offspring from HFD and chow-fed ancestors (F0) were taken to generate the third generation (F3) offspring.

We show here that 9 weeks maternal HFD exposure induces obesogenic (e.g., increased body weight, increased adiposity, insulin resistance, and altered lipid profile), addictive-like phenotypes (e.g., increased consumption of alcohol, enhanced sensitivity to cocaine, and amphetamine) as well as hypodopaminergic state of the mesolimbic reward system over three generations in the absence of any further HFD exposure. Our findings demonstrate a true transgenerational inheritance via the male germline since the effect is also persistent in the non-exposed F3 generation. Furthermore, by the third generation, a clear sex-dependent effect emerges, where females show addictive like behaviors while males show obesogenic phenotypes.

While the present study was in a mouse model, this observation may help to increase awareness about healthy food habits during pregnancy and breastfeeding.

To understand the underlying mechanisms for such inheritance, we analyzed the global DNA methylation pattern in F1 and F2 sperm. Although the whole genome methylome of HFD groups is massively affected in both generations, a clear methylation signature is not conserved across generations. This indicates that sperm methylome might not constitute the major carrier of the observed phenotypes, suggesting a more complex mode of transmission.

Our findings highlight the long-term impact of maternal fat rich food intake during preconception, gestation and lactation on the development of obesity and addiction across multiple generations. Our work provides further insight into the role of early life nutrition in the causes of obesity and addiction. While the present study was in a mouse model, this observation may help to increase awareness about healthy food habits during pregnancy and breastfeeding to secure better health for the next generations.

Enjoyed this blog post? Read the full article in Translational Psychiatry.