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.