Ulf Risérus

Fatty acid composition of serum lipids predicts the development of the metabolic syndrome in men

Aims/hypothesisTypes of dietary fat have been related to components of the metabolic syndrome. Serum fatty acid composition mainly reflects dietary fat intake, but also endogenous fatty acid synthesis catalysed by Δ-desaturases. It is not known whether alterations of fatty acid composition or desaturase activities predict metabolic syndrome.Materials and methodsWe prospectively evaluated fatty acid composition in serum cholesteryl esters and estimated desaturase activities in 1,558 50-year-old men taking part in a population-based cohort study. The follow-up time was 20 years. Stearoyl-CoA desaturase (SCD-1), Δ6 (D6D) and Δ5 (D5D) desaturases were estimated as precursor to fatty acid ratios.ResultsHigh activity of estimated SCD-1 (odds ratio=1.29, p<0.05) and D6D (odds ratio=1.35, p<0.05), as well as low estimated D5D activity (odds ratio=0.71, p<0.001) predicted the development of metabolic syndrome (as defined by the National Cholesterol Education Program). The predictive value of D5D activity was independent of lifestyle factors (smoking, BMI and physical activity), whereas the risk associated with higher SCD-1 and D6D activities was mainly explained by obesity. Among those developing metabolic syndrome (119 out of 706) during follow-up, the proportions of fatty acids 14:0, 16:0, 16:1 (n−7), 18:1 (n−9), 18:3 (n−6) and 20:3 (n−6) were increased at baseline, while 18:2 (n−6) was decreased (p<0.05 for all).Conclusions/interpretationSerum fatty acid composition predicts the long-term development of the metabolic syndrome, and D5D activity may be particularly important in this process. Our results suggest a role of dietary fat quality in the development of metabolic syndrome, but the possibility that altered fatty acid composition, partly secondary to genetic or hormonal factors, should also be considered.

Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

OBJECTIVE— Pharmacological use of peroxisome proliferator–activated receptor (PPAR)δ agonists and transgenic overexpression of PPARδ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS— The PPARδ agonist (10 mg o.d. GW501516), a comparator PPARα agonist (20 μg o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS— Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (−30%), apolipoprotein B (−26%), LDL cholesterol (−23%), and insulin (−11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P < 0.05) and 30% reduction in urinary isoprostanes (P = 0.01) were also observed. Except for a lowering of triglycerides (−30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO2 directly originating from the fat content of the meal was increased (P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased. CONCLUSIONS— The PPARδ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle.