Protein metabolism adapts during caloric restriction (CR) to minimize protein loss, and it is unclear whether greater fat stores favorably affect this response. We sought to determine whether protein metabolism is related to degree of obesity and whether the response to CR is impacted by pre-CR adiposity level. Whole body protein metabolism was studied in 12 obese women over a wide range of BMI (30-53 kg/m(2)) as inpatients using [1-(13)C]leucine as a tracer following 5 days of a weight-maintaining diet and then after 30 days of CR (1,400 kcal deficit with maintained protein intake). When expressed as total rates, per body weight (BW) or per fat-free mass (FFM), leucine rate of appearance (Ra), and nonoxidative leucine disposal (NOLD) were significantly higher in the individuals with a greater degree of obesity (P < 0.05). Leucine oxidation (Rox) was also higher in more highly obese women when expressed as a total rate (P < 0.05) but not if expressed per BW or FFM. CR reduced BW, FFM, and fat mass (P < 0.001), and declines were relatively similar between individuals. CR reduced Ra (P < 0.001), NOLD (P < 0.01), and Rox (P < 0.05), and the relative decline was not affected by differences in fat mass. CR-induced declines were significant even when Ra and NOLD were normalized to BW or FFM. We conclude that fat mass, like FFM, is a key determinant of protein turnover. However, during CR, higher fat mass does not favorably alter the response of protein metabolism and does not mitigate the loss of FFM.