nists have been characterized largely in terms of their effects on lipids and glucose metabolism, whereas little has been reported about effects on amino acid metabolism. We studied responses to the PPAR␣ agonist WY 14,643 (30 mol⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 wk) in rats fed a saturated fat diet. Plasma and urine were analyzed with proton NMR. Plasma amino acids were measured using HPLC, and hepatic gene expression was assessed with DNA arrays. The high-fat diet elevated plasma levels of insulin and triglycerides (TG), and WY 14,643 treatment ameliorated this insulin resistance and dyslipidemia, lowering plasma insulin and TG levels. In addition, treatment decreased body weight gain, without altering cumulative food intake, and increased liver mass. WY 14,643 increased plasma levels of 12 of 22 amino acids, including glucogenic and some ketogenic amino acids, whereas arginine was significantly decreased. There was no alteration in branched-chain amino acid levels. Compared with the fat-fed control animals, WY 14,643-treated animals had raised plasma urea and ammonia levels as well as raised urine levels of N-methylnicotinamide and dimethylglycine. WY 14,643 induced changes in a number of key genes involved in amino acid metabolism in addition to expected effects on hepatic genes involved in lipid catabolism and ketone body formation. In conclusion, the present results suggest that, in rodents, effects of pharmacological PPAR␣ activation extend beyond control of lipid metabolism to include important effects on whole body amino acid mobilization and hepatic amino acid metabolism.peroxisome proliferator-activated receptor-␣ PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␣ (PPAR␣) agonists are used clinically to treat dyslipidemia and to reduce the risk of cardiovascular complications (7). The beneficial effects of these agents appear to be most significant in patients with insulin resistance and diabetes (32). It is clear that a major and primary action of PPAR␣ activation is the transcriptional regulation of genes involved in lipid metabolism (36). However, the effects of PPAR␣ activation may not be limited to lipid metabolism, given the established interactions between the major substrate classes (19), e.g., the glucose-fatty acid cycle (29) and the glucose-alanine cycle (10). In terms of glucose metabolism, an important physiological role of PPAR␣ is suggested by the hypoglycemia in response to prolonged fasting developed by mice lacking PPAR␣ (17). Furthermore, treatment of fat-fed rats with the selective PPAR␣ agonist WY 14,643 resulted in increases in whole body and skeletal muscle insulin-stimulated glucose utilization, with the enhancement in muscle insulin sensitivity related to the degree of reduction in local lipid accumulation (39). Surprisingly little has been reported concerning effects of PPAR␣ activation on amino acid metabolism, although work based largely on analysis of mRNA in mouse liver (23) suggests an important influence on the handling of this substrate class.The aim of the present study was to provide...

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ChemInform Abstract Hydrolysis of the vinyl ether group in the three isomeric vinyl ether compounds (VI) -(VIII), obtained from 5-chloro-2-pentanone (I) as shown in the reaction scheme, leads to the formation of 6-(2-pyridyl)-2-hexanone (IX) and has been studied in acetic acid, hydrochloric acid, and biphosphate ion buffer solutions. (Kinetics, rate constant ratio).

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