URINARY ORGANIC-ACID PROFILES IN OBESE (OB OB) MICE - INDICATIONS FOR THE IMPAIRED OMEGA-OXIDATION OF FATTY-ACIDS

As a means of generating an hypothesis to explain genetic obesity of the C57BL/6J ob/ob mouse, we used gas chromatography-mass spectrometry to compare the urinary organic acid profiles of obese (ob/ob) and lean (+/?) mice on both a chow and a chemically simplified diet. More than 60 peaks were found and quantified; 45 peaks were identified. No acid was excreted in greater amounts by lean mice and none was excreted exclusively by either lean or obese mice. When normalized to body weight (obese mice being 40% heavier) and to creatinine excretion (30% greater in obese mice), however, only the daily excretion of malate, 2-hydroxyglutarate, aconitate, 3-hydroxy-3-methylglutarate, oxalate, ethylmalonate, and 4-hydroxyphenylacetate were significantly greater in obese mice. When allowed to eat only an all-fat (Crisco) diet for 4 days, the excretion of adipate rose 10-fold in lean mice, but only threefold in obese mice. Adipate excretion by Zucker rats also increased on the Crisco diet, but was indistinguishable between lean and fatty rats, suggesting that ω-oxidation might be impaired in obese mice but not in fatty rats. This suggestion complements an earlier proposal that a comparative increase in ethylamalonate excretion, which was also characteristic of fatty Zucker rats, might be explained by an increased concentration of butyryl-CoA due to inadequate β-oxidation. An impairment of ω-oxidation in the obese mouse may also explain why urinary 3-hydroxy-3-methylglutarate, which is derived from short chain products of β-oxidation, is increased in obese mice but not in fatty rats. Thus we suggest that ethylmalonate excretion may be increased in both models of rodent obesity because of an increased concentration of its precursor, butyryl-CoA, which is also the optimal primer for fatty acid synthesis. © 1992.