Forty-eight morbidly obese patients were placed on a very low calorie (800 kcal) formula diet (OPTIFAST) for a 10-week period with the goal of achieving 10% weight loss within this time. Weekly serum leptin measurements were performed to determine whether changes in this adipose protein would serve as a useful marker of acute and chronic weight loss compliance. In the basal state, serum leptin averaged 56.9 +/- 5.8 ng/ml (SE) in the 24 successful (S) patients, and 67.7 +/- 6.7 ng/ml in the non-successful (N-S) group. During the first week of weight loss there was little change in leptin despite an average weight loss of 2.2%, but after 4 weeks serum leptin decreased by 36% in the S group, and 20% in the N-S group. After 10 weeks, the S group averaged 13.6% weight loss and the serum leptin decreased to 50% of starting levels. In the 24 N-S patients, the mean weight loss was 7.0%, and serum leptin decreased by 22%, remaining unchanged in the final 6 weeks despite a weight loss of 3.6% in this time. On a week-to-week basis serum leptin changed concordantly with weight loss only two-thirds of the time. In a subgroup of 14 patients (8 S+6 N-S), serial assessments of serum leptin, insulin and tumor necrosis factor-alpha (TNF-alpha) were performed. Serum insulin levels decreased with weight loss similar in magnitude to that noted for leptin; however, the insulin changes occurred more rapidly. Serum TNF-alpha also decreased with weight loss, but the weekly changes were more erratic, with a concordance rate of only 48%. In summary, serum leptin, insulin and TNF-alpha all decreased during a rapid weight loss program but at differing rates and variability, precluding their usefulness as markers of week-to-week weight loss compliance.