sity implies a failure of autoregulatory homeostatic responses to caloric excess. We studied the mechanisms, effectiveness, and limits of such responses in six lean (21.9 Ϯ 1.3 kg/m 2 ), healthy men based in a metabolic suite for 17 wk of progressive intermittent overfeeding (OF) (3 wk, baseline; 3 wk, 20% OF; 1 wk, ad libitum; 3 wk, 40% OF; 1 wk, ad libitum; 3 wk, 60% OF; 3 wk, ad libitum). Body composition was assessed by a four-compartment model using dual X-ray absorptiometry, deuterium dilution, and plethysmography. Magnetic resonance imaging assessed subcutaneous/visceral fat at abdominal level at baseline and at the end of 60% OF. Energy intake was assessed throughout, energy expenditure (EE) and substrate oxidation rates were measured repeatedly by whole body calorimetry (calEE), and free-living EE (TEE) was measured by doubly labeled water at baseline and after 60% OF. At the end of 60% OF, calEE and TEE had increased by just 11.4% (P ϭ 0.001) and 16.2% (P ϭ 0.001), respectively. Weight and body fat (fat mass) had increased by 5.98 kg (8.8%, P ϭ 0.001) and 3.31 kg (22.6%, P ϭ 0.01), respectively. The relative increase in visceral fat (32.6%, P ϭ 0.02) exceeded that of subcutaneous fat (13.3%, P ϭ 0.002) in the abdominal region. The computed energy cost of tissue accretion differed from the excess ingested by only 13.1% (using calEE) and 11.6% (using TEE), indicating an absence of effective dissipative mechanisms. We conclude that elevations in EE provide very limited autoregulatory capacity in body weight regulation, and that regulation must be dominated by hypothalamic modulation of energy intake. This result supports present conclusions from genetic studies in which all known causes of human obesity are related to defects in the regulation of appetite. energy balance; body composition; whole body calorimetry; doubly labeled water; overfeeding; dissipative mechanisms OVEREATING, WHETHER CHRONIC or episodic, produces a positive energy balance and favors the accretion of new tissues, particularly fat (35,49). The efficiency of innate autoregulatory mechanisms that attempt to maintain body weight homeostasis has been explored extensively during the last century since the earliest experiments published by Neumann in 1902 (30) and Gulick in 1922 (14). These suggested the existence of energy dissipative mechanisms (termed luxuskonsumption) able to dispose of part of the energy excess as heat and decrease the storage of energy as fat. These two overfeeding studies were conducted on only one subject, and the authors claimed that an increase in energy expenditure (EE) dissipated the extra energy available and prevented weight gain. Forbes (11) reexamined the relationship between weight gain and excess energy intake in these two studies and observed that the slope of the regression line between weight gain and excess energy intake was close to the predicted cost of weight gain. Since then, numerous studies performed under experimental (3, 8, 17, 22, 24 -26, 37, 41) and nonexperimental settings (5,28,33,45) ha...