Evidence for Leptin Binding to Proteins in Serum of Rodents and Humans: Modulation With Obesity

Abstract

Many hormones circulate bound to serum proteins that modulate ligand bioactivity and bioavailability. To understand the biology of leptin action, we investigated the presence of leptin binding proteins in serum. 125I-labeled leptin binds competitively to at least three serum macromolecules with molecular masses of approximately 85, approximately 176, and approximately 240 kDa in rodents and approximately 176 and approximately 240 kDa in humans. The ability to bind appears to involve sulfhydryl/disulfide interactions because it is inhibited under reducing conditions. When serum is added to recombinant 125I-leptin, there is a shift in sedimentation of 125I-leptin as analyzed by sucrose gradient centrifugation from approximately S1.9 to approximately S4.3. This shift is markedly attenuated in serum from obese mice (ob/ob, db/db, brown-fat ablated, gold-thioglucose treated, high-fat fed) compared with that from nonobese controls. The size distribution of endogenous serum leptin as determined by radioimmunoassay (RIA) after sucrose gradient centrifugation is also consistent with saturation of binding in hyperleptinemic obesity. In humans, free leptin increases with BMI. Thus, in lean rodents and humans a large proportion of leptin circulates bound to several serum proteins. Free leptin is increased in serum of obese subjects, which may alter leptin bioactivity, transport, and/or clearance.

Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction

“…This state might be explained by the reduction in leptin turnover and degradation (Houseknecht et al 1996) or stimulation of the HPTA in response to low TH concentrations in rats, dogs, and humans (Mazaki-Tovi et al 2010). In contrast to these results, the serum concentration of leptin was found to be decreased during hypothyroidism (Ahmed et al 2012b).…”

A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women

“…A soluble form of the leptin receptor exists in serum. Serum LBA has been described in both humans and rodents (Houseknecht et al 1996;Sinha et al 1996); at least a proportion of this binding is attributable to the soluble extracellular domain of the leptin receptor (Liu et al 1997). Modulation of leptin activity by a soluble form of the receptor is consistent with observations in other cytokine systems, including interleukin 1, tumour necrosis factor-α and growth hormone.…”

Nutritional regulation of leptin signaling

“…Binding proteins have a role in modulating the availability of free hormone (the generally metabolically active form) for interaction with target tissues. Evidence for leptin-binding proteins in human and rodent circulation was shown [35,36]. In lean subjects, a large proportion of leptin circulates bound to several serum proteins, and free leptin is increased in the serum of obese subjects [35,36].…”