The adaptation to fasting reduces muscle protein breakdown by switching from a carbohydrate to fat fuel economy in normal man. With the discovery of T3 and the observation that its formation from T4 was reduced significantly during starvation, it was proposed that T3 mediated many of these changes. To examine this possibility, otherwise healthy, obese subjects were fasted for 10 days and supplemented with T3 the last 3 days of the fast to bring circulating T3 levels within normal prefasting (weight maintenance) levels. The effects of the same dose of T3 for 3 days were tested during the last 3 days of a 10-day weight maintenance diet for comparison. Both metabolic rate and CO2 production decreased as expected with fasting and did not increase after T3 supplementation. Hepatic glucose appearance rates fell with fasting and increased significantly during T4 supplementation, but not to prefasting levels. Urinary urea nitrogen excretion decreased significantly with fasting and decreased further with T3 supplementation. Lysine appearance did not change during fasting or T3 supplementation, but leucine appearance decreased with T3 supplementation during fasting. These observations suggest that the fall in serum T3 during fasting may not mediate the observed decreases in protein breakdown that occur during fasting and prolonged starvation, but may instead initiate the fall in hepatic glucose appearance.