Short-term influences of dichloroacetate on genetically hyperlipemic rats

The effects of short-term (7 days) administration of dichloroacetate (DCA) on carbohydrate and lipid metabolism in the Zucker obese and lean rat were investigated. Metabolic effects of the drug were more pronounced in the obese than in the lean rat. DCA decreased fasting blood glucose concentrations in both lean and obese rats, but more so in the fat animals, probably because of higher initial levels. The hypoglycemic action of DCA is likely attributable to a direct effect on liver and peripheral tissues and not to an indirect action caused by a decrease in the glucagon-to-insulin ratio because the drug induced just the opposite effect. DCA decreased plasma triglycerides (TG) and free fatty acids (FFA) in the hyperlipemic rats but not in lean rats. Intrahepatic triglyceride content diminished after drug treatment in fat rats, suggesting decreased hepatic TG synthesis. Hyperketonemia, induced in both lean and fat rats by DCA treatment, was also greater in the obese animal. This response was probably caused by accelerated hepatic ketone body production due to increased beta-oxidation, and not to enhance FFA substrate supply. These data demonstrate that DCA is capable of correcting many of the underlying abnormalities in carbohydrate and fat metabolism in the obese Zucker rat.