The purpose of this study was to assess the potential impact of weight loss up to a state of plateau on symptoms of depression. Eleven obese men (mean body mass index (BMI)=33.4 kg.m(-2), mean age=38 y) participated in this repeated-measures, within-subjects, clinical intervention. They were subjected to a weight-loss program that consisted of a supervised diet and exercise clinical intervention. The phases investigated were (i) baseline; (ii) after 5+/-1 kg loss of body mass (phase 1); (iii) after 10+/-1 kg weight loss (phase 2); and (iv) at resistance to further weight loss (plateau). At each phase of the weight-reducing program, glucose homeostasis markers were determined using an oral glucose tolerance test (OGTT). Serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3), and free thyroxine (fT4) concentrations were also measured and the Beck Depression Inventory (BDI) was administered. The weight loss plateau occurred after 7.4+/-1.9 months of intervention and corresponded to a loss of 11.2% of initial body weight (93.9% of which was from fat stores). This amount of weight loss induced a significant decrease in resting metabolic rate (RMR) (p<0.05) and a significant increase in desire to eat (p<0.05) and in depression symptoms (p<0.01) compared with baseline. Intriguingly, the glucose area below fasting values (GABF) at plateau was significantly higher as compared with other phases of the program (p<0.01). We found a strong negative correlation (r=-0.77, p<0.01) between the change in glucose concentrations at 180 min of the OGTT and the change in BDI scores between plateau and baseline values. Similarly, highly significant relationships were found between the change in T3 or fT4 concentrations and the change in BDI scores (r=-0.71 and r=-0.68, respectively; p<0.01). Weight loss until plateauing is associated with a trend toward hypoglycemia at the end of the oral glucose challenge and with a decrease in T3 and fT4 levels. These physiological changes are shown to be highly linked with the increase in depression symptoms observed at plateau. Taken together, these data emphasize the relevance of caution and reasonable objectives when prescribing a weight reduction program to obese individuals.