Urinary organic acid profiles in fatty Zucker rats: indications for impaired oxidation of butyrate and hexanoate.

The urinary excretion of 45 organic acids, monitored by gas-liquid chromatography, was compared in fatty (fa/fa) and lean (Fa/?) Zucker rats maintained on a chemically simplified diet. At the age of 6, 16, and 22 weeks, fatty rats excreted more of the various organic acids than their lean counterparts. However, the greatest difference was in the excretion of ethylmalonate, even when excretion data were normalized to body weight. The next highest excretion difference was in adipate and an unknown compound, and the third highest in pyruvate. A second group of rats examined at 7 weeks also excreted an excess of these four acids, as well as glucuronate and indole-3-acetate. The excessive excretion of ethylmalonate and adipate, which is characteristic of human genetic defects in short- and medium-chain fatty acid oxidation, suggested that the oxidation of butyrate and hexanoate might be impaired in the fatty rat. Thus, as a test of their capacity to oxidize medium- and short-chain fatty acids, two groups of fatty and lean rats were transferred to diets enriched with either trioctanoylglyceride, a medium-chain triglyceride (MCT), or sodium butyrate, a short-chain fatty acid. Both lean and fatty rats on the MCT diet, but only the lean rats on the butyrate-enriched diet, increased their excretion of adipate. However, on both the MCT and butyrate diet, ethylmalonate excretion increased only in lean rats, almost reaching amounts found previously in fatty rats. These results suggest that the fatty rat has an impairment of the beta-oxidation of butyrate and hexanoate, a defect that might increase intracellular concentrations of butyryl-CoA, the optimal primer for the synthesis of long-chain fatty acids.