Short-term energy deprivation reduces leptin concentrations and alters the levels of circulating hormones of the hypothalamic–pituitary–peripheral axis in lean subjects. Whether the reduction in leptin concentration during long-term weight loss in obese individuals is linked to the same neuroendocrine changes seen in lean, leptin-sensitive subjects remains to be fully clarified.

In this study, 24 overweight and obese adults (16 women and eight men; body mass index (BMI): 27.5–38.0 kg/m²) were prescribed a hypocaloric diet (−500 kcal/day) and were randomized to receive recombinant methionyl leptin (n=18, metreleptin, 10 mg/day self-injected s.c.) or placebo (n=6, same volume and time as metreleptin) for 6 months.

Metreleptin administration did not affect weight loss beyond that induced by hypocaloric diet alone (P for interaction=0.341) but increased the serum concentrations of total leptin by six- to eight-fold (P<0.001) and led to the generation of anti-leptin antibodies. Despite free leptin concentration (P for interaction=0.041) increasing from 9±1 ng/ml at baseline to 43±15 and 36±12 ng/ml at 3 and 6 months, respectively, changes in circulating hormones of the thyroid and IGF axes at 3 and 6 months were not significantly different in the placebo- and metreleptin-treated groups.

Leptin does not likely mediate changes in neuroendocrine function in response to weight loss induced by a mild hypocaloric diet in overweight and obese subjects.