Background: Pharmacological use of peroxisome proliferator-activated receptor-δ (PPARδ) 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.Methods: The PPARδ agonist (GW501516, 10mg OD), a comparator PPARα agonist (GW590735, 20μg OD) and placebo were given in a double-blind, randomized, 3-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-hour 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 …

Hypertriglyceridemia and insulin resistance in the setting of obesity, i.e. the metabolic syndrome, are thought related to ectopic fat storage and impaired regulation of fat oxidation. Rodent models suggest that increased PPARdelta function may correct these abnormalities. Design/Methods: Double-blind, randomized, 3-parallel group (n = 6 in each group), 2-week study of PPARdelta agonist ( GW501516 –10mg), PPARalpha agonist ( GW590735 –20ug) and placebo. Men with a waist > 95cm, BMI > 27, TG > 100mg/dl < 400mg/dl, and HDLc < 50 mg/dl were included. Blood lipids, fatty acids, serum insulin and liver fat content (MRI) were measured at baseline and termination of study, while oral 13 C-palmitate-labeled fat-feeding allowed post-meal examination of plasma NEFA metabolism and oxidation ( 13 CO 2 exhalation). Skeletal muscle biopsies were taken to monitor transcript regulation of fat oxidation pathways. Results: The PPARdelta group revealed reduction of LDLc, apoB and TG by 23%, 21%, and 31%, respectively and of plasma NEFA, without any deterioration of insulin and glucose homeostasis. Comparable TG reduction in PPARalpha (27%), with modest apoB reductions (−13%) were not accompanied by NEFA reductions. Hepatic fat was significantly reduced in the PPARdelta group only (p = 0.04). After the labeled fat meal, cumulative exhaled 13 CO 2 was increased (p = 0.03; enhanced fat catabolism) and accompanied by increased mRNA expression of skeletal muscle CPT1b only in the PPARδ group. Summary: Short term administration of a selective PPARdelta agonist decreased TG, apoB, LDL-C and NEFA concentrations. Increased peripheral fatty acid uptake and oxidation may partly explain these benefits.

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-gamma (PPAR gamma) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and Delta 6- and Delta 5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and Delta 5-desaturase but not Delta 6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPAR gamma carrier, SCD and Delta 5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPAR gamma mutation supports a pivotal role of PPAR gamma function in SCD regulation.

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-γ (PPARγ) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and Δ6- and Δ5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and Δ5-desaturase but not Δ6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARγ carrier, SCD and Δ5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARγ mutation supports a pivotal role of PPARγ function in SCD regulation.

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-γ (PPARγ) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and Δ6- and Δ5-desaturase activity, using product-to …