We read with great interest the article by Bruce et al. regarding the effect in a mouse model of maternal high-fat feeding on the development of nonalcoholic fatty liver disease (NAFLD) in adult offspring.1 The authors observed that maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism. Although the authors reported only female mice data because their data from males and females showed the same pattern, we consider that some issues deserve further discussion.
We evaluated in a rat model the impact of developmental and long-term adult nutritional insult of high-fat diet (HFD) on liver steatosis and abdominal fat accumulation, and compared male and female offspring of dams exposed to different nutrition treatments (HFD versus standard chow diet [SCD]) to examine the hypothesis that nutritional insults during fetal development can result in a fatty liver phenotype in adulthood. Interestingly, we replicated the findings of Bruce et al., and observed in addition that maternal HFD feeding modified the sexual dimorphic effect of HFD on liver steatosis and abdominal fat content observed in offspring of mothers fed an SCD.
Female Wistar rats were randomly assigned to either ad libitum HFD solid diet2 or SCD. Dams were fed 15 days before conception and during gestation and lactation. The 17-week-old offspring were assigned either ad libitum HFD or SCD for an 18-week period, generating eight experimental groups (Fig. 1). At the completion of the study, animals were sacrificed and abdominal fat tissue (intraperitoneal and retroperitoneal) was measured by direct weighing; the degree of liver steatosis was assessed as previously reported.3
In the group of HFD-fed offspring of SCD-fed dams, we observed a clear sexually dimorphic effect of HFD feeding because female rats developed a significantly greater degree of fatty change than male rats; this finding was similar when we analyzed abdominal fat content (Fig. 1). However, in the group of HFD-fed offspring of HFD-fed dams, the sexual differences in both fatty liver degree and abdominal fat content were not observed, although the degree of liver steatosis was lower in female offspring of HFD-fed dams versus those of SCD-fed dams (Fig. 1). Interestingly, these effects were independent of dam body weight, which suggests a specific effect of the diet.
In conclusion, the female-specific consequences of feeding HFD (a finding previously reported in other rat models of NAFLD4) deserves further investigations as the underlying mechanisms involved in the sex difference are not clear. Otherwise, our study provides additional evidence of the effect of maternal high-fat nutrition on the liver and abdominal fat accumulation in either male or female HFD-fed offspring, thus suggesting the importance of the developmental programming that can induce the NAFLD phenotype completely independent of sex differences. This finding strongly supports the hypothesis of Bruce et al. about the “priming” effect of maternal mitochondria on metabolic pathways associated with NAFLD, which is compatible with our recent findings of a decrease in mitochondrial DNA copy number in adolescents with insulin resistance5 and in newborns with abnormal birth weight,6 which are two well-known risk factors for metabolic syndrome in adults.