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Genome-Wide Association Studies of Estimated Fatty Acid Desaturase Activity in Serum and Adipose Tissue in Elderly Individuals: Associations with Insulin Sensitivity.

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 ?-5-desaturase (D5D), ?-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.

SUBMITTER: Marklund M

PROVIDER: S-EPMC6266021 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genome-Wide Association Studies of Estimated Fatty Acid Desaturase Activity in Serum and Adipose Tissue in Elderly Individuals: Associations with Insulin Sensitivity.

Marklund Matti M Morris Andrew P AP Mahajan Anubha A Ingelsson Erik E Lindgren Cecilia M CM Lind Lars L Risérus Ulf U

Nutrients 20181117 11

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 (<i>n</i> = 1453) ...[more]

PMID: 30453627

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Project description:Background and aimsInsulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD.MethodsAdipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants.ResultsProinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes.ConclusionsSystemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

Project description:ContextAccurate assessment of insulin sensitivity may better identify individuals at increased risk of cardio-metabolic diseases.ObjectivesTo examine whether a combination of anthropometric, biochemical and imaging measures can better estimate insulin sensitivity index (ISI) and provide improved prediction of cardio-metabolic risk, in comparison to HOMA-IR.Design and participantsHealthy male volunteers (96 Chinese, 80 Malay, 77 Indian), 21 to 40 years, body mass index 18-30 kg/m(2). Predicted ISI (ISI-cal) was generated using 45 randomly selected Chinese through stepwise multiple linear regression, and validated in the rest using non-parametric correlation (Kendall's tau ?). In an independent longitudinal cohort, ISI-cal and HOMA-IR were compared for prediction of diabetes and cardiovascular disease (CVD), using ROC curves.SettingThe study was conducted in a university academic medical centre.Outcome measuresISI measured by hyperinsulinemic euglycemic glucose clamp, along with anthropometric measurements, biochemical assessment and imaging; incident diabetes and CVD.ResultsA combination of fasting insulin, serum triglycerides and waist-to-hip ratio (WHR) provided the best estimate of clamp-derived ISI (adjusted R(2) 0.58 versus 0.32 HOMA-IR). In an independent cohort, ROC areas under the curve were 0.77±0.02 ISI-cal versus 0.76±0.02 HOMA-IR (p>0.05) for incident diabetes, and 0.74±0.03 ISI-cal versus 0.61±0.03 HOMA-IR (p<0.001) for incident CVD. ISI-cal also had greater sensitivity than defined metabolic syndrome in predicting CVD, with a four-fold increase in the risk of CVD independent of metabolic syndrome.ConclusionsTriglycerides and WHR, combined with fasting insulin levels, provide a better estimate of current insulin resistance state and improved identification of individuals with future risk of CVD, compared to HOMA-IR. This may be useful for estimating insulin sensitivity and cardio-metabolic risk in clinical and epidemiological settings.

Dataset Information

Genome-Wide Association Studies of Estimated Fatty Acid Desaturase Activity in Serum and Adipose Tissue in Elderly Individuals: Associations with Insulin Sensitivity.

Publications

Genome-Wide Association Studies of Estimated Fatty Acid Desaturase Activity in Serum and Adipose Tissue in Elderly Individuals: Associations with Insulin Sensitivity.

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