In Sprague-Dawley rats, fatty acid synthase (FAS) activity is suppressed by dietary fat. To test the hypothesis that a defect in regulation of de novo fatty acid synthesis exists in massive obesity, we investigated the effect of diet on FAS mRNA levels in genetically obese JCR:LA-corpulent (cp) rats. We also determined levels of mRNA encoding adipsin, a fat cell-derived protein possibly associated with lipid metabolism. Hepatic FAS mRNA levels were elevated five-fold in obese compared to lean cp rats and were unsuppressed by dietary fat. Dietary sucrose increased FAS mRNA levels in lean cp rats, but, in contrast to Sprague-Dawley rats, little deposition of lipid resulted. Adipsin mRNA levels were fivefold lower in obese cp and Sprague-Dawley rats than in lean cp rats and were unaffected by diet. We conclude that exaggerated de novo fatty acid synthesis may play a major role in the pathogenesis of obesity in obese JCR:LA-corpulent rats.