l-165041 and Body-Weight

A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARγ target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARα target genes indicating that their in vivo effects stemmed from an activation of both PPARα and γ. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.

Topics: Adipocytes; Animals; Antineoplastic Agents; Benzoxazoles; Body Weight; Calorimetry; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Partial Agonism; Drug Screening Assays, Antitumor; Fibric Acids; Fibroblasts; Gene Expression Profiling; Humans; Insulin Resistance; Intra-Abdominal Fat; Liver; Mice; Mice, Inbred C57BL; Models, Molecular; PPAR alpha; PPAR gamma; Propionates; Stereoisomerism; Structure-Activity Relationship; Urea

Peroxisome proliferator-activated receptor delta promotes fatty acid catabolism and energy expenditure in skeletal muscle and adipose tissues. A ligand for PPARdelta is required to activate PPARdelta function. Polyunsaturated fatty acids are potential ligands for PPARdelta activation. The current experiment was designed to determine the potential for PUFA, particularly from dietary fish oil, to activate porcine PPARdelta in vivo. Transgenic mice were generated to overexpress porcine PPARdelta in the adipose tissue. Mice were fed a high-saturated fat (13% beef tallow), or high-unsaturated fat (13% fish oil) diet, or a diet containing 4 mg/kg of a PPARdelta ligand (L165041) for 4 mo. Compared with beef tallow feeding, fish oil feeding reduced fat mass and decreased (P < 0.05) plasma triacylglycerol and FFA concentrations in the transgenic mice. Adipose tissue expression of genes involved in adipogenesis (i.e., lipoprotein lipase and adipocyte fatty acid-binding protein) was decreased in transgenic mice fed fish oil or the PPARdelta ligand. In the same mice, expression of the lipolytic gene, hormone-sensitive lipase was increased (P < 0.05). Fish oil feeding also stimulated expression of genes participating in fatty acid oxidation in the liver of transgenic mice compared with wild-type mice. Overall, these results indicate that PUFA may serve as natural and effective regulators of lipid catabolism in vivo and many of these effects may be generated from activation of PPARdelta.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats, Unsaturated; Eating; Fatty Acids, Nonesterified; Fish Oils; Ion Channels; Ligands; Lipolysis; Lipoprotein Lipase; Liver; Mice; Mice, Transgenic; Mitochondrial Proteins; Organ Size; Phenoxyacetates; PPAR delta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Esterase; Sterol Regulatory Element Binding Protein 1; Triglycerides; Uncoupling Protein 3