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Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans

Chan, J.L., Matarese, G., Shetty, G.K., Raciti, P., Kelesidis, I., Aufiero, D., De Rosa, V., Perna, F., Fontana, S., Mantzoros, C.S.
Proceedings of the National Academy of Sciences of the United States of America 2006 v.103 no.22 pp. 8481-8486
leptin, hormonal regulation, fasting, hormone secretion, luteinizing hormone, metabolism, body weight, immune response, leukocytes, neurosecretory system, T-lymphocytes, body composition, women, mononuclear leukocytes
To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by approximately 80% from a midphysiologic (14.7 ± 2.6 ng/ml) to a low-physiologic (2.8 ± 0.3 ng/ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 ± 2.0 ng/ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and/or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin's physiologic targets.