title: Regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans.
abstract: 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).
authors.affiliation: Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Chan
authors.forename: Susann
authors.initials: S
authors.lastname: Blüher
authors.forename: Nikos
authors.initials: N
authors.lastname: Yiannakouris
authors.forename: Marc A
authors.initials: MA
authors.lastname: Suchard
authors.forename: Jurgen
authors.initials: J
authors.lastname: Kratzsch
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015992:Body Mass Index; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology*; D003430:Cross-Sectional Studies; D004958:Estradiol / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000097:blood*; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine / Q000097:blood; D054411:Receptors, Leptin; D012727:Sex Characteristics; D013739:Testosterone / Q000097:blood*; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D054411:Receptors, Leptin; D013739:Testosterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D006854:Hydrocortisone