Obesity is associated with both insulin resistance and hyperinsulinemia. Initially hyperinsulinemia compensates for the insulin resistance and thereby maintains normal glucose homeostasis. Obesity is also associated with increased tissue triglyceride (TG) content. To determine whether both insulin resistance and hyperinsulinemia might be secondary to increased tissue TG, we studied correlations between TG content of skeletal muscle, liver, and pancreas and plasma insulin, plasma [insulin] x [glucose], and beta-cell function in four rat models with widely varying fat content: obese Zucker diabetic fatty rats, free-feeding lean Wistar rats, hyperleptinemic Wistar rats with profound tissue lipopenia, and rats pair fed to hyperleptinemics. Correlation coefficients >0.9 (P < 0.05) were obtained among TG of skeletal muscle, liver, and pancreas and among plasma insulin, [insulin] x [glucose] product, and beta-cell function as gauged by basal, glucose-stimulated, and arginine-stimulated insulin secretion by the isolated perfused pancreas. Although these correlations cannot prove cause and effect, they are consistent with the hypothesis that the TG content of tissues sets the level of both insulin resistance and insulin production.