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 omega-oxidation might be impaired in obese mice but not in fatty rats. This suggestion complements an earlier proposal that a comparative increase in ethylmalonate excretion, which was also characteristic of fatty Zucker rats, might be explained by an increased concentration of butyryl-CoA due to inadequate beta-oxidation. An impairment of omega-oxidation in the obese mouse may also explain why urinary 3-hydroxy-3-methylglutarate, which is derived from short chain products of beta-oxidation, is increased in obese mice but not in fatty rats.(ABSTRACT TRUNCATED AT 250 WORDS)