OBJECTIVE-Pharmacological use of peroxisome proliferatoractivated receptor (PPAR)␦ agonists and transgenic overexpression of PPAR␦ 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, 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 GW501516showed statistically significant reductions in fasting plasma triglycerides (Ϫ30%), apolipoprotein B (Ϫ26%), LDL cholesterol (Ϫ23%), and insulin (Ϫ11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P Ͻ 0.05) and 30% reduction in urinary isoprostanes (P ϭ 0.01) were also observed. Except for a lowering of triglycerides (Ϫ30%, P Ͻ 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased (P Ͻ 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.CONCLUSIONS-The PPAR␦ 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. Diabetes 57: 332-339, 2008
Objectives-Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)␦ expression. In parallel, PPAR␦ agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models. Methods and Results-Healthy volunteers were allocated placebo (nϭ6) or PPAR␦ agonist (GW501516) at 2.5 mg (nϭ9) or 10 mg (nϭ9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (Pϭ0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (Pϭ0.02). HDLc was enhanced in both treatment groups (2.5 mg Pϭ0.004, 10 mg PϽ0.001) when compared with the decrease in the placebo group (Ϫ11.5Ϯ1.6%, Pϭ0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (Pϭ0.002). However, LpL expression remained unchanged. Conclusions-This is the first report of a PPAR␦ agonist administered to man. In this small study, GW501516 significantly
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Solid phase peptide synthesis (SPPS), first proposed by R. B. Merrifield in 1962, has evolved over three decades into a tremendously powerful method for the preparation of peptides and small proteins. An absolute prerequisite for successful syntheses in all solid phase schemes is that reactions which accumulate solid supported products, and by the very nature of the technique contaminating by-products, must proceed cleanly and efficiently. During the earlier years of SPPS this optimal situation was not always achieved, primarily due to contaminated reagents and ill-defined polymers in combination with poorly flexible protection strategies. As the methods of SPPS gained popularity and more widespread application, reagents and protection strategies were improved and refined. However, reports of notable successful syntheses were accompanied by then unexplained failures, which have since been collectively termed ‘difficult peptides’. This chapter describes how an intrinsic understanding behind the occurrence of ‘difficult peptides’ has accumulated, leading to a general synthetic solution—the utilization of a backbone amide protection strategy. Within a few years of the introduction of SPPS, it was recognized that the assembly of some peptide sequences posed a special synthetic problem. The main feature evident during these syntheses was a sudden decrease in reaction kinetics, leading to incomplete amino-acylation by activated amino acid residues. The unreacted sites were readily detected by the Kaiser test for free amine; however, couplings showed no significant improvement even upon repeated or prolonged reaction. Efficient reactions are known to occur within a fully solvated peptide-polymer matrix, where reagent penetration is rapid and unhindered. This optimal situation no longer exists during the assembly of a difficult peptide, where the normally accessible solid phase reaction matrix becomes partially inaccessible during assembly. This situation arises suddenly, typically 6-12 residues into the synthesis, and may then persist for a number of cycles before easing, or in extreme cases remain throughout the completion of the assembly. The crude products are particularly poor if slower coupling β-branched residues (isoleucine, valine, threonine) are introduced after the onset of synthetic difficulties. The principles underlying the occurrence of difficult peptide sequences have for many years been the focus of intense debate and research. An intrinsic feature of the numerous ideas proposed is that aggregation occurs resulting in poor solvation within the peptide-polymer matrix.
No abstract
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