<i>FADS2</i> Over expression Promotes Metabolic Syndrome in Mice: Influence of Maternal Dietary Polyunsaturated Fatty Acid Composition (2016)

Accumulating evidence from human and animal studies indicates that risk of developing metabolic syndrome (MSx) is strongly influenced by maternal genotype and the nutritional environment encountered during fetal and early postnatal development. In addition to the well‐established effects of over nutrition, the fatty acid composition of the diet, particularly the n6:n3 polyunsaturated fatty acid (PUFA) ratio, has been postulated to play an important role in the development of MSx. However, results from dietary PUFA intervention studies on metabolic health have been inconsistent, perhaps in part due to individual and population differences in endogenous PUFA metabolism. Indeed, common FADS2 haplotypes and elevated serum indices of PUFA metabolism by its gene product, delta‐6 desaturase (D6D), also predict obesity and MSx in children and adult populations, though any causal relationship remains to be established. To directly investigate the effect of FADS2 expression on metabolic phenotype, we generated mice with global transgenic over expression of FADS2 (CMV promoter), backcrossed for 8 generations on a FVB background. FADS2 ‐tg mice exhibit elevated serum and tissue PUFA product/precursor ratios reflective of systemic D6D hyperactivity similar to those associated with FADS2 haplotypes and cardiometabolic risk in epidemiological studies. When maintained on a standard chow diet (Harlan 2918; 18% Kcals Fat), FADS2 ‐tg mice develop progressive obesity, glucose intolerance, insulin resistance and hyperlipidemia beginning at 1–2 months of age compared to age‐matched FVB wild‐type (WT) mice on the same chow diet. Importantly, linoleic acid (18:2n6) represents the majority (91%) of PUFA in 2918 chow, generating a dietary n6:n3 PUFA ratio of &gt;10:1, similar to the modern “western” diet. Based on clinical evidence for potentially beneficial effects of perinatal n3‐PUFA supplementation on infant metabolic status, we tested the hypothesis that reducing this ratio to ~3:1 in the maternal diet of FADS2 ‐tg mice would attenuate development of MSx in her offspring. FADS2 ‐tg females were fed 2918 chow supplemented with 2% flaxseed oil (providing ~1% w/w n3 α‐linolenic acid; ALA) beginning 2 weeks prior to pairing with a WT male until litters were weaned. Offspring were maintained on the standard 2918 chow diet after weaning, and compared to litters from the same mother without ALA supplementation. Interestingly, maternal ALA supplementation significantly normalized weight gain and glucose tolerance to near WT levels in male, but not female, offspring for up to 2 months post weaning on the chow diet. Food intake was similar across groups, actually trending higher in the offspring from the ALA supplemented pregnancy. Taken together, these studies suggest a causal link between FADS2 expression and the development of MSx, and reveal sex‐specific benefits of prenatal n3‐PUFA supplementation in this context. The cellular mechanisms responsible for MSx induced by FADS2 over expression, and its suppression by maternal ALA supplementation, are currently being investigated in our laboratory. Support or Funding Information Supported by grants from the USDA and Colorado Agricultural Experimental Station to AJC.