Injection of norepinephrine (NE) (25 micrograms/100 g body wt) caused a similar rise in metabolic rate in lean and obese (fa/fa) Zucker rats, but 3-day fasting suppressed the response in lean rats and enhanced the rise in obese mutants. Triiodothyronine (T3) injection (10 micrograms/100 g body wt) caused a significantly greater rise in oxygen consumption (Vo2) in obese than lean rats, but the response was attenuated by fasting in all animals. The thermic response to a single meal of either mixed composition, carbohydrate, or protein (40 kJ) was much smaller in obese rats than lean, but the response to the mixed nutrient meal was similar for all rats after a 3-day fast. Refeeding 3-day fasted lean rats with a single carbohydrate meal (40 kJ) caused a rise in plasma T3 levels after 3 h and a delayed increase in metabolic rate 24 h later. Injection of NE instead of refeeding caused a similar delayed rise in metabolic rate. Carbohydrate refeeding had no effect on plasma T3 levels or oxygen consumption in 3-day fasted obese Zuckers, but injection of NE did produce a significant increase in metabolic rate after 24 h. Refeeding 3-day fasted rats with protein (40 kJ) caused a rise in oxygen consumption 24 h later in lean animals but had no effect in obese animals. The data from lean Zucker rats confirm previous findings in Sprague-Dawley rats and suggest that the thermic response to refeeding involves a complex interaction between the sympathetic nervous system and thyroid hormones. Obese Zuckers responded normally to NE and T3, indicating that their reduced thermogenesis after food may be due to insensitivity to nutrient availability or an inability to activate the sympathetic nervous system.