Regulation of Circulating Soluble Leptin Receptor Levels By Gender, Adiposity, Sex Steroids, and Leptin
Observational and Interventional Studies in Humans
- Jean L. Chan1,
- Susann Blüher1,
- Nikos Yiannakouris2,
- Marc A. Suchard3,
- Jurgen Kratzsch4 and
- Christos S. Mantzoros1
- 1Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- 2Department of Home Economics and Ecology, Harokopio University, Athens, Greece
- 3Department of Biomathematics, UCLA School of Medicine, Los Angeles, California
- 4Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
Leptin is an adipocyte-secreted hormone important in energy homeostasis and diverse physiological processes. A circulating soluble form of the leptin receptor [soluble leptin receptor (sOB-R)] is the main leptin-binding protein and determinant of free leptin index (FLI), the presumed biologically active form of leptin. We performed observational and interventional studies to elucidate the regulation of sOB-R and FLI in humans. In a cross-sectional study (n = 118), leptin, gender, and adiposity were significant determinants of sOB-R. By multivariate analysis, estradiol (E2) and testosterone predict sOB-R, whereas insulin predicts leptin and FLI. In a frequent-sampling study (n = 6), sOB-R followed a significant circadian rhythm inverse to that of leptin, suggesting that leptin’s biological activity may have an even more pronounced diurnal variation than originally thought. A 72-h fast in eight men decreased leptin levels by 80% and increased lymphocyte expression of leptin receptor mRNA and serum sOB-R levels by 100%. Physiological and pharmacological doses of recombinant-methionyl human leptin (rhLeptin) administered to fasted men prevented the fasting-induced increase of sOB-R levels, and pharmacological doses resulted in a decrease in sOB-R levels. These studies provide evidence that sOB-R is regulated by gender, adiposity, hormones, and rhLeptin administration. This may have important implications for the biological activity of leptin in disease states associated with abnormal leptin levels (e.g., obesity and anorexia nervosa).
Address correspondence and reprint requests to Christos S. Mantzoros, Division of Endocrinology RN 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, Massachusetts 02215. E-mail:.
Received for publication 12 February 2002 and accepted in revised form 18 April 2002.
C.S.M. has received honoraria for speaking engagements and grant support from Amgen and Novartis and is a paid consultant of Diagnostics Systems Laboratory.
FM, percent fat mass; BIDMC, Beth Israel Deaconess Medical Center; CSF, cerebrospinal fluid; E2, estradiol; ELISA, enzyme-linked immunosorbent assay; FFM, fat-free mass; FLI, free leptin index; FT, free testosterone; GCRC, General Clinical Research Center; LIFA, ligand-immunofunctional assay; rhLeptin, recombinant-methionyl human leptin; RIA, radioimmunoassay; sOB-R, soluble leptin receptor.