Glucose uptake into heart and skeletal muscle and white and brown adipose tissue is reduced in mice with gold thioglucose-induced obesity. After acute dieting (40% of lean control uptake) for 18 days, glucose uptake into tissues remains low despite consistently elevated serum insulin levels. This reduced glucose uptake may be a consequence of the raised serum fatty acid levels produced by dieting. When the reduced weight obese mice are pair-fed with lean controls, they gain weight. Glucose uptake into both muscle and adipose tissues is markedly increased, and the insulin resistance of both previous obesity and recent relative starvation is rapidly overcome at the level of the glucose uptake, but serum insulin levels and insulin secretion from islets of Langerhans isolated from these animals remain high. To maintain reduced weight, previously obese animals were fed 80% of lean control intake. In this situation, glucose uptake into the four tissues studied remained reduced (compared to lean controls), consistent with relative starvation. While tissue glucose uptake increases after dieting and re-feeding of obese animals, serum insulin levels remain high, indicating persistence of a degree of insulin resistance. Reduced-weight obese animals are energy-efficient in that they gain excess weight on the control intake.