The aim of this pilot study was to determine whether it was possible to prevent the metabolic and behavioral vulnerability related to weight regain generally observed in a reduced-obese state with a supervised diet-exercise clinical intervention. In this regard, the anthropometric and physiological effects of a body weight loss program were studied in 11 obese men and the impact of weight loss on appetite was measured by visual analogue scales (VAS) and by the use of a standardized buffet-type meal. All the measurements were assessed at the beginning of the intervention (baseline), after 5+/-1 kg body weight loss (Phase 1) and after 10+/-1 kg body weight loss (Phase 2). In Phase 1 and Phase 2, respectively, the diet-exercise intervention significantly reduced fat mass, waist circumference, fasting insulin and glucose, resting heart rate, and resting systolic and diastolic blood pressures. The diet-exercise intervention also preserved fat-free mass, resting metabolic rate, resting respiratory quotient, and immune function. No significant difference was observed in appetite sensations between the three time points, either measured with VAS in the fasting state or with the satiety quotient (SQ) calculation. Thus, this study provides evidence that obesity can be managed by adequate and specific lifestyle changes leading to clinical benefits while avoiding side effects potentially promoting an increase in energy intake and body weight relapse.