Fat and carbohydrate intake over three generations modify growth, metabolism and cardiovascular phenotype in female mice in an age-related manner

Environmental challenges such as a high fat diet during pregnancy can induce changes in offspring growth, metabolism and cardiovascular function. However, challenges that are sustained over several generations can induce progressive compensatory metabolic adjustments in young adults. It is not known if such effects persist during ageing. We investigated whether diets with different fat and carbohydrate contents over three generations modifies markers of ageing. Female C57BL/6 F0 mice were fed diets containing 5% or 21% fat (w/w) throughout pregnancy and lactation. Female offspring were fed the same diet as their dams until the F3 generation. In each generation, body weight, 24-hour food intake were recorded weekly, and plasma metabolites were measured by colorimetric assays, blood pressure by tail cuff plethysmography and vasoconstriction by myography on postnatal day 90 or 456. There was little effect of diet or generation on phenotypic markers in day 90 adults. There was a significant increase in whole body, liver and heart weight with ageing (d456) in the F3 21% fat group compared to the F1 and F3 5% groups. Fasting plasma glucose concentration was significantly increased with ageing in the 5% group in the F3 generation and in the 21% group in both generations. There was a significant effect of diet and generation on ex-vivo vasoconstriction in ageing females. Differences in dietary fat may induce metabolic compensation in young adults that persist over three generations. However, such compensatory effects decline during ageing

Schematic illustrating the effect of multiple generation exposure to increased dietary fat and carbohydrate on changes in fasting plasma glucose levels with ageing.

<p>The effect of the 21% is evident form the initial generation exposed to the diet and remains unchanged following multiple generations on the diet. Exposure to the 5% diet leads to few or no effects in the initial generation exposed, however following a sustained exposure to the diet for three generations, a similar profile is reached to that of the 21% exposed group.</p

(A) Body weight and (B) energy intake in young (D90) and ageing (D456) adult mice.

<p>Values are mean ± SEM (n = 5 to 7 per dietary group per generation). Statistical comparison between groups, within each age, was carried out by ANOVA with diet and generation as fixed factors, with LSD <i>post hoc</i> correction. Means with different letters differ significantly (P < 0.05). *Means significantly different (P<0.05) between D456 and D90, determined by Student’s unpaired t-test (P<0.05).</p

(A) Liver and (B) heart weight in young (D90) and ageing (D456) adult mice.

<p>Values are mean ± SEM (n = 5 to 7 per dietary group per generation). Statistical comparison between groups, within each age, was carried out by ANOVA with diet and generation as fixed factors, with LSD <i>post hoc</i> correction. Means with different letters differ significantly (P < 0.05). *Means significantly different (P<0.05) between D456 and D90, determined by Student’s unpaired t-test (P<0.05).</p

Pe induced vasoconstriction (pEC50) in young (D90) and ageing (D456) adult mice.

<p>Values are mean ± SEM (n = 5 to 7 per dietary group per generation). Statistical comparison between groups, within each age, was carried out by ANOVA with diet and generation as fixed factors, with LSD <i>post hoc</i> correction. Means with different letters differ significantly (P < 0.05). *Means significantly different (P<0.05) between D456 and D90, determined by Student’s unpaired t-test (P<0.05).</p

Compositions of the diets.

<p>NI, not included in the diet.</p><p>*RM1.</p><p>Compositions of the diets.</p

DNA methylation of SIRT1, the longevity gene, in blood from children at 5–7 years exhibits temporal stability and predicts adiposity in adolescence

<p>Our preliminary findings show that the methylation status of specific CpG loci in the peroxisomal proliferator-gamma-co-activator-(PGC)-1α promoter in blood at age 5-7 years predicted later adiposity in the children age 14 years. PGC1α is a downstream effector of Sirtuin 1 (SIRT1), a gene which has been shown to influence lifespan in a range of species and which is known to regulate energy metabolism in different tissues.</p> <p>We, therefore, have investigated the temporal stability of specific CpG loci within the promoter of SIRT1 during childhood and whether the CpG loci that exhibited temporal stability predicted adiposity.</p