Linoleic and a linolenic fatty acid consumption over three generations exert cumulative regulation of hepatic expression of genes related to lipid metabolism

Abstract The essential fatty acids, omega 3 and omega 6, consumed during pregnancy can benefit maternal and offspring health. For instance, they could activate a network of genes related to the nuclear receptor peroxisome proliferators activated receptor a (Ppara) and sterol regulatory element binding transcription factor 1 (Srebf1), which
play a role in fatty acid oxidation and lipogenesis. The present study aimed to investigate the effects of diets with different omega 3 per omega 6 ratio consumed over three generations on blood biochemical parameters and hepatic expression of Ppara and Srebf1 related genes. During three consecutive generations adult Wistar rats were evaluated in the postpartum period (21 days after parturition).  Regardless of prenatal dietary omega 3 per omega 6 ratio, an up regulation in liver tissue was observed for Rxra, Lxra and Srebf1 and a down regulation for Fasn in all the evaluated generations. The diet with higher omega 3 per omega 6 ratio decreased triacylglycerol serum levels and resulted in a constant non esterified fatty acid level. Our results indicated that the PUFAs effect on the modulation of genes related to fatty acid oxidation and lipogenesis is cumulative through generations. (Authors abstract)

It has been proposed that nutrients such as omega 3 fatty acids could influence offspring development and heath. They are major sources of energy, acting to control the fluidity, permeability and conformation of cellular membranes. The polyunsaturated fatty acids (PUFAs) are especially important because they serve as precursors of important bioactive compounds such as prostacyclins, prostaglandins, thromboxanes and leukotrienes besides their role in structural functions. During pregnancy in mammals, PUFAs are required for embryo and oocyte development, cell growth and differentiation . In this regard, studies have suggested the need for feeding different ratios of omega 6 and omega 3  during pregnancy. For instance, off spring of dams fed with a high lard (i.e., saturated fat) diet during pregnancy and lactation were more susceptible to metabolic syndrome, including dyslipidemia, increased blood pressure and adiposity. Recently, it was demonstrated that a high omega 3 diet reversed the hypertension, hyperlipidemia and adiposity that was induced by consumption of a high fat diet from weaning in 6 month old male Wistar rats. The objective of this study was to evaluate the effect of diets with different n3 to n6 ratio in successive generations on blood parameters and hepatic expression level of some nuclear receptors and target genes involved in lipid metabolism.

The experimental diets offered to the animals in this study contained high amounts of PUFAs, almost 50per cent  in the C diet, and more than 60 per cent  in the H diet. The H group had more ALA and its metabolites, eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA) than the C group; while the animals that received the C diet had greater concentrations of LA and its metabolite arachidonic acid (AA) indicating activity of desaturases and elongases.  In the present study, only the C group decreased Ppara mRNA abundance from G0 to F1 and F2 generations, the other groups maintained their expression levels. In contrast, the expression of Srebf1 increased from G0 through F2 regardless of experimental group. A similar profile was observed for Lxra and Rxra expression, concerning with the studies cited above, providing evidence of the regulation of Srebf1 via Lxra activation. In the liver, Ppara activation represses Srebf1 expression  and the decrease in Ppara coupled with the increase in Srebf1 expression across generations seems to support the mechanistic regulation between these transcription factors. The experimental diets did not alter the plasma glucose concentration, in accordance with other recent studies and indicating that chronic feeding of diets rich in PUFAs do not alter the glucose metabolism and its plasma concentration. It has already been shown that feeding animals with n3 and n6 diets is effective in lowering plasma triacylglycerol levels. A lack of difference in pregnancy rate between the groups and generations suggests that the ratio between n6 and n3 did not influence female fertility. The greater pup mean weight of the F1 generation in the group fed with the omega 3 rich diet than controls, which were fed with the omega 6 rich diet, demonstrates that maternal consumption of omega 3 PUFAs during pregnancy had an effect on fetal and offspring growth and development. The reduction in pup mean weight in the control group between G0 to F1, and its maintenance in F2, indicated that more attention should be given to the n3 to n6 ratio during the perinatal period. In conclusion, feeding animals with PUFAs allowed for an initial study of the trans generational control of hepatic lipo genesis and metabolism. There is clear evidence of cumulative effects throughout generations, independent of the PUFAs source, at least in part via up and down regulation of lipid metabolism related genes. (Editors comments)