Abstract
Fatty acid desaturases (FADS) catalyze the formation of unsaturated fatty acids and have been related to insulin sensitivity (IS). FADS activities differ between tissues and are influenced by genetic factors that may impact the link to IS. Genome-wide association studies of δ-5-desaturase (D5D), δ-6-desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD) activities (estimated by product-to-precursor ratios of fatty acids analyzed by gas chromatography) in serum cholesterol esters (n = 1453) and adipose tissue (n = 783, all men) were performed in two Swedish population-based cohorts. Genome-wide significant associated loci were evaluated for associations with IS measured with a hyperinsulinemic euglycemic clamp (n = 554). Variants at the FADS1 were strongly associated with D5D in both cholesterol esters (p = 1.9 × 10−70) and adipose tissue (p = 1.1 × 10−27). Variants in three further loci were associated with D6D in cholesterol esters (FADS2, p = 3.0 × 10−67; PDXDCI, p = 4.8 × 10−8; and near MC4R, p = 3.7 × 10−8) but no associations with D6D in adipose tissue attained genome-wide significance. One locus was associated with SCD in adipose tissue (PKDL1, p = 2.2 × 10−19). Genetic variants near MC4R were associated with IS (p = 3.8 × 10−3). The FADS cluster was the main genetic determinant of estimated FADS activity. However, fatty acid (FA) ratios in adipose tissue and cholesterol esters represent FADS activities in separate tissues and are thus influenced by different genetic factors with potential varying effects on IS.
Highlights
Fatty acid desaturases (FADS) catalyze the formation of mono- and polyunsaturated fatty acid and influence the fatty acid (FA) composition of the blood stream and in adipose tissue (AT).The major human FADS include δ-5-desaturase (D5D), δ-6-desaturase (D6D) and δ-9-desaturase or stearoyl-CoA desaturase-1 (SCD)
This could lead to effects on cell membranes and altered levels of polyunsaturated fatty acids (PUFA) which function as ligands for a variety of transcription factors [3]
Estimated D6D activity has likewise previously been positively associated to obesity [34,35] and it can be speculated that the observed associations of rs9957425 with desaturase activity, Body mass index (BMI) and insulin sensitivity (IS) are due to MC4R-mediated effects on food and fatty acid intake, which could influence FA proportions and thereby the FA ratio used for estimating D6D activity
Summary
Fatty acid desaturases (FADS) catalyze the formation of mono- and polyunsaturated fatty acid and influence the fatty acid (FA) composition of the blood stream and in adipose tissue (AT).The major human FADS include δ-5-desaturase (D5D), δ-6-desaturase (D6D) and δ-9-desaturase or stearoyl-CoA desaturase-1 (SCD). Since in vivo measurement of enzyme activity can be challenging, ratios of substrate and product concentrations are commonly used to estimate activities of SCD, D6D and D5D [1] Both circulating fatty acid composition and estimated FADS activities have previously been associated with insulin sensitivity (IS) and incidence of type 2 diabetes (T2D), the mechanisms underlying these relationships have not been fully determined [2]. It has been suggested that the effects of FADS on IS are mediated by alterations in FA compositions This could lead to effects on cell membranes (influencing insulin receptor binding and affinity, translocation of glucose transporters and intercellular signaling) and altered levels of polyunsaturated fatty acids (PUFA) which function as ligands for a variety of transcription factors [3]. Polymorphisms in the genes encoding for FADS have been was associated with fasting glucose levels and estimated β-cell function in a large-scale meta-analysis of genome-wide association studies (GWAS) [4]
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