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Endocrine and Metabolic Effects of Physiologic r-metHuLeptin Administration during Acute Caloric Deprivation in Normal-Weight Women

Program in Nutritional Metabolism (S.S., B.C., P.K., S.G.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Amgen Inc. (A.M.D.), Thousand Oaks, California 91319

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit Street, LON 207, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.

Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 ± 0.2 vs. 9.6 ± 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (–0.6 ± 0.1 vs. –0.2 ± 0.1 kg, P = 0.03). Both overnight LH area (38.9 ± 21.5 vs. 1.2 ± 11.1 µIU/ml·min, P = 0.05) and LH peak width increased (15.8 ± 7.1 vs. –2.3 ± 6.7 min, P = 0.06) and LH pulsatility decreased (–2.0 ± 0.9 vs. 1.0 ± 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (–1.06 ± 0.27 vs. –0.32 ± 0.18 µIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = –0.76, P = 0.03) but not placebo (r = –0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation.

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