The usual covariates of adiposity--adipocyte size, total body fat, and food intake--were experimentally dissociated using three new models of altered adipose tissue morphology in the rat. It was thereby possible to test the hypothesis that plasma immunoreactive insulin level (IRI) is a function of mean adipocyte size. In two of the models, experimental and control rats differ substantially in total body fat but show no difference in mean adipocyte size. In these models, no difference in plasma IRI was found between experimental and control animals. In a third model, experimental and control rats differ in mean adipocyte size but not in total body fat or daily food intake. In this model, plasma IRI was found to differ between experimental and control rats. These observations demonstrate a close link between adipocyte size and plasma IRI and suggest that the hyperinsulinemia and peripheral insulin resistance of obesity are more likely due to adipocyte hypertrophy than to increases in total body fat or daily food intake.