Abstract
Omega-6 fatty acids have been shown to exert pro-adipogenic effects whereas omega-3 fatty acids work in opposition. Increasing intakes of LA (linoleic acid; omega-6) vs ALA (alpha-linolenic acid; omega-3) in Western diets has led to the hypothesis that consumption of this diet during pregnancy may be contributing to adverse offspring health. This study investigated the effects of feeding a maternal dietary LA:ALA ratio similar to that of the Western diet (9:1) compared to a proposed ‘ideal’ ratio (~1:1.5), at two total fat levels (18% vs 36% fat w/w), on growth and lipogenic gene expression in the offspring. Female Wistar rats were assigned to one of the four experimental groups throughout gestation and lactation. Offspring were culled at 1 and 2 weeks of age for sample collection. Offspring of dams consuming a -36% fat diet were ~20% lighter than those exposed to a 18% fat diet (P<0.001). Male, but not female, liver weight at 1 week was ~13% heavier, and had increased glycogen (P<0.05), in offspring exposed to high LA (P<0.01). Hepatic expression of lipogenic genes suggested an increase in lipogenesis in male offspring exposed to a 36% fat maternal diet and in female offspring exposed to a low LA diet, via increases in the expression of Fasn and Srebf1. Sexually dimorphic responses to altered maternal diet appeared to persist until two weeks-of-age. In conclusion, whilst maternal total fat content predominantly affected offspring growth, fatty acid ratio and total fat content had sexually dimorphic effects on offspring liver weight and composition.
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Key Points
Data from observational studies in humans and animal models provide supporting evidence that suggests high intakes of omega-6 PUFA during pregnancy could have negative effects on metabolic health of the progeny (13,14,15). However, the results of these studies have not been consistent. The results of pre-clinical studies are also limited by the use of diets with much higher omega-6:omega-3 PUFA ratios and/or absolute PUFA contents than those encountered in typical human diets. Furthermore, offspring often continue to have access to the same diet as their mother so that any effects observed cannot be clearly attributed to dietary fatty acid exposure during the gestation and lactation periods (16,17,18). The aim of this study, therefore, was to investigate the effects of feeding a maternal dietary LA:ALA ratio similar to that of the Western diet (9:1) (6), compared to a proposed ‘ideal’ ratio of 1:1.5 (19,20) on growth and lipogenic gene expression in the offspring. Since total dietary PUFA intake also influences PUFA metabolism (9,10), we also investigated the effect of feeding each dietary fat ratio at either 18% fat w/w (in line with dietary recommendations (21)) or at a higher fat level of 36% fat w/w. A rat model was utilised to achieve the study objectives by allowing for tight control of dietary manipulation as well as invasive end points.
This study has demonstrated that altering the fat content and/or LA:ALA ratio of the maternal diet during pregnancy and lactation resulted in significant alteration in the circulating fatty acid profile of dams in the absence of any significant effects on maternal bodyweight or body composition. Exposure to a 36% fat diet during gestation and lactation was, however, associated with lower offspring bodyweight from birth, which persisted to 2 weeks of age. This suggests that increased dietary fat intake during pregnancy and lactation can compromise growth of the progeny, irrespective of the type of fat consumed. In addition, alterations in the fat content and/or composition of the maternal diet had transient effects on offspring body composition and hepatic gene expression, effects which were also sex-specific.
Maternal fatty acid profiles after 4 weeks on the experimental diets largely reflected dietary composition, confirming that the dietary intervention had the desired effect on maternal circulating fatty acid composition. These changes persisted after a further 6 weeks of exposure to the diets and, as expected, the dietary LA:ALA ratio had a greater impact on the maternal blood omega-6 and omega-3 status than total dietary fat content.
In conclusion, we have demonstrated that exposure to a 36% fat diet during gestation and lactation is associated with persistent growth restriction in both male and female offspring irrespective of maternal dietary fatty acid composition. Growth restriction has been associated with a plethora of metabolic disturbances later in life (54,55,56) and transient alterations in gene expression have been suggested as a mechanism for programming changes in metabolic processes within tissues as well as the morphology of the tissues themselves (1) . In this study, offspring are still exposed to the experimental diets via the dams milk, and further studies in offspring at older ages are required to assess whether the changes in growth, hepatic gene expression and liver weights in the current study are associated with phenotypic changes that persist once offspring are no longer exposed directly to the altered diet composition. In addition, analysis of lipogenic pathway and adipokines targets at the protein level, as well as whole transcriptome analysis, may yield useful information about their regulation and the extent to which these experimental diets programme other metabolic and regulatory pathways in the liver. Finally, the longevity of these perturbations into later life, especially when presented with secondary metabolic challenges such as aging, prolonged high-fat feeding or in the case of female offspring, pregnancy, remains to be elucidated.