Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition

Abstract

Maternal overnutrition has been associated with increased susceptibility to develop obesity and neurological disorders later in life. Most epidemiological as well as experimental studies have focused on the metabolic consequences across generations following an early developmental nutritional insult. Recently, it has been shown that maternal high-fat diet (HFD) affects third-generation female body mass via the paternal lineage. We showed here that the offspring born to HFD ancestors displayed addictive-like behaviors as well as obesity and insulin resistance up to the third generation in the absence of any further exposure to HFD. These findings, implicate that the male germ line is a major player in transferring phenotypic traits. These behavioral and physiological alterations were paralleled by reduced striatal dopamine levels and increased dopamine 2 receptor density. Interestingly, by the third generation a clear gender segregation emerged, where females showed addictive-like behaviors while male HFD offspring showed an obesogenic phenotype. However, methylome profiling of F1 and F2 sperm revealed no significant difference between the offspring groups, suggesting that the sperm methylome might not be the major carrier for the transmission of the phenotypes observed in our mouse model. Together, our study for the first time demonstrates that maternal HFD insult causes sustained alterations of the mesolimbic dopaminergic system suggestive of a predisposition to develop obesity and addictive-like behaviors across multiple generations.

Advances in epigenetics link genetics to the environment and disease

“…DNA methylation has been suggested as a potential mechanism for these effects, and retroelements and some genes involved in neurological and metabolic disorders remain methylated during the wave of DNA demethylation in human primordial germ cells 122 . However, a recent report in which a high-fat diet induced insulin resistance, obesity and addictive-like behaviours up to the third generation did not identify heritable changes in the DNA methylome 123 . Other chromatin components might also be involved.…”

Perinatal exposure to maternal obesity: Lasting cardiometabolic impact on offspring

“…Animal models have demonstrated that exposure to a HFD in utero and during lactation results in increased fat preference and food intake in offspring compared to offspring fed a balanced chow diet prior to weaning or during lactation alone 87,91,101,136 . A preference for fatty and sugary foods mediated by the mesolimbic dopamine reward circuitry may explain, in part, the increased risk for obesity in offspring exposed to overnutrition early in development 27,137‐139 . However, the mesolimbic reward circuit is only one circuit driving offspring eating behavior and hyperphagia.…”

Präkonzeptionelle Prävention

“…Eine aktuelle prospektive Beobachtungsstudie zeigte, dass neben einem hohen Ausgangsgewicht der Mutter vor Schwangerschaftsbeginn auch ein hoher BMI des werdenden Vaters mit einem höheren BMI des Kindes im Alter von 7 Jahren im Zusammenhang stand 40 . Kürzlich konnte in einem Mausmodell beobachtet werden, dass eine fettreiche Ernährung vor der Paarung, während der Schwangerschaft und der Stillzeit zu einer höheren Rate an Übergewicht, Insulinresistenz, Fettstoffwechselstörungen sowie suchtähnlichen Verhaltensweisen bis in die zweite Generation führte 41 .…”