Interaction of Fads2 Genotype and Dietary Essential Fatty Acid Intake on Metabolic Risk in Mice

Abstract

Polyunsaturated fatty acids (PUFAs) play important roles in inflammation, cardiovascular, and metabolic function. However, controversy exists regarding effects of dietary PUFA intake on metabolic risk due to inconsistent results from studies in the literature. We hypothesized that some of this controversy results from variations in individuals' metabolism of dietary essential PUFAs, suggested by altered cardiometabolic risk profiles in populations with polymorphisms in a key PUFA metabolism gene, FADS2. To address this, we developed colonies of mice with global heterozygous knockout (low), wild‐type (WT; medium) or mild transgenic overexpression (high) of FADS2 expression. Mice were fed a standardized high‐fat (40% kcal) diet containing dietary essential PUFAs at ~7% kcals provided as mostly linoleic acid (18:2n6, LA; as corn oil; 57:1 n6:n3), α‐linolenic acid (18:3n3; as flax oil; 1:4 n6:n3) or a 50/50 blend of each providing 1:1 n6:n3 PUFAs. Effects on glucose tolerance were monitored over 4 months, followed by analysis of liver fat deposition and macrophage content. In mice with WT FADS2 expression, enrichment of a high‐fat diet with n6‐PUFA augmented glucose intolerance, weight gain, and hepatic inflammation; while n3‐PUFA tended to have the opposite effect. The same metabolic syndrome phenotype was augmented by high (transgenic) FADS2 overexpression and attenuated by low FADS2 (knockdown) expression compared to WT controls when dietary n3:n6 PUFA composition was balanced 1:1, demonstrating a potent influence of FADS2 expression on metabolic phenotype and hepatic inflammation. However, dietary imbalance of n3:n6 PUFA intake, either toward higher n3 or n6 PUFA intake, tended to mitigate the effect of higher or low FADS2 expression. Taken together, these results support a complex interaction of FADS2 expression and dietary PUFA intake on metabolic risk, prompting future study of FADS2 haplotypes as potentially relevant criteria for individualized dietary recommendations.Support or Funding InformationThis project is supported by AFRI Grant # 2014‐06594 from the USDA National Institute of Food and Agriculture.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.