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

doi:10.1073/pnas.0505429103

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

*Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
^‡Gruppo di ImmunoEndocrinologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS–CNR), 80131 Naples, Italy; and
^§Cattedra di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare and
^¶Cattedra di Malattie dell’Apparato Respiratorio, Dipartimento di Medicina Clinica e Sperimantale, Università di Napoli “Frederico II,” 80131 Naples, Italy

Edited by Jeffrey M. Friedman, The Rockefeller University, New York, NY, and approved April 13, 2006
↵ ^†J.L.C. and G.M. contributed equally to this work. (received for review June 28, 2005)

Abstract

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 ≈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.

Footnotes

^‖To whom correspondence should be addressed at:
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, ST816, Boston, MA 02215.
E-mail: cmantzor{at}bidmc.harvard.edu
Author contributions: J.L.C. and C.S.M. designed research; J.L.C., G.M., G.K.S., P.R., I.K., D.A., V.D.R., F.P., and S.F. performed research; G.M. contributed new reagents/analytic tools; J.L.C., G.M., P.R., and C.M. analyzed data; and J.L.C., G.M., and C.S.M. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

ACTH,

adrenocorticotropic hormone;

FFA,

free fatty acid;

FSH,

follicle-stimulating hormone;

T3,

triiodothyronine;

IGF-BP,

IGF-binding protein;

LH,

luteinizing hormone;

PBMC,

peripheral blood mononuclear cell;

PRA,

plasma renin activity;

TSH,

thyroid-stimulating hormone.