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The soluble leptin receptor

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The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10-dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders.

Introduction

Changes in eating behaviour towards high caloric food and a decreased disposition to physical activity have led to an increased incidence of the metabolic syndrome both in industrialized countries and in newly industrialized as well as developing countries. Moreover, the coincidence of metabolic disorders, such as obesity, diabetes, hypertension and disorders of lipid metabolism, is associated with an increased risk for myocardial infarction and stroke.

The 16 kDa adipocytokine leptin [1], [2] is mainly produced by the white adipose tissue [3]. It is involved in the central regulation of food intake [4], [5], modulates peripheral metabolic processes [6], [7], [8] and influences reproductive function [9], [10], [11] as well as the immune response [12], [13], [14], [15]. Leptin concentrations in the serum of obese subjects are distinctly increased compared with normal-weight subjects ∗[16], [17]. This has been attributed to the often reported correlation between whole body fat mass and the amounts of leptin synthesized by adipose tissue. In addition to the extent of leptin synthesis by adipose tissue, and the amount of expression of membrane-anchored, signal-transducing leptin receptors (OB-Rs), leptin binding proteins affect the efficacy of the adipocytokine and leptin sensitivity of different tissues. The soluble leptin receptor (sOB-R) is the main binding protein for leptin in human blood [18]. Therefore, sOB-R can modulate the bioavailability and, consequently, the cellular effects of the peptide hormone leptin [19].

Section snippets

The soluble leptin receptor is a leptin receptor isoform

Leptin actions are mediated through the leptin receptor (OB-R) [20]. The OB-R possesses a single transmembrane domain and is closely related to the gp130 subunit of the IL-6-receptor-complex, the GCSF- as well as the LIF-receptor [20]. On the basis of this relationship, the OB-R has been assigned to the class I cytokine receptor family.

So far, four different membrane-anchored OB-R isoforms (Table 1) have been described in humans (OB-Rfl, OB-R219.1, OB-R219.2 and OB-R219.3). They have identical

The soluble leptin receptor and leptin resistance

The pathophysiological condition of leptin resistance [21] is especially characterized by decreased leptin effects on the regulation of food intake and energy expenditure. This condition is often seen in obese individuals who seem to have no identified mutation of the leptin receptor. Paradoxically, it is also not associated with decreased leptin synthesis, as its concentration in overweight or even obese individuals is actually increased ∗[16], [17]. In analogy to insulin resistance, increased

Detection, generation and regulation of the soluble leptin receptor

Sinha et al. [44] primarily confirmed the existence of leptin-binding proteins in human plasma and, therefore, this group was capable of differentiating between free and bound leptin. In these investigations, the soluble leptin receptor was identified as a possible leptin-binding protein. Lammert et al. [18] were the first to identify the sOB-R as the main binding protein for leptin in human blood. Further proteins, such as the protease inhibitor α2-makroglobulin and members of the

Functional effects of the soluble leptin receptor

The soluble leptin receptor is the main binding protein for leptin in human blood [18], and therefore is capable of pivotally modulating its bioavailability.

In general, circulating soluble forms of membrane-anchored receptors can have both agonistic and antagonistic functions, although the latter seems to prevail. One prominent representative of soluble receptors with agonistic effects is the soluble IL-6 receptor. When binding IL-6, the sIL-6R can interact with gp130, the signal transducing

Summary

In general, both decreased and increased serum sOB-R concentrations seem to mirror the pathophysiological state of leptin resistance. The term leptin resistance currently stands for impaired or absent leptin sensitivity despite increased endogenous leptin concentrations but disregards alterations of serum sOB-R concentrations. Leptin resistance can be systemic or restricted to distinct organs such as the hypothalamus, liver or skeletal muscle [60], ∗[61], ∗[77]. In most cases, it is assumed

Conflict of interests

Michael Schaab discloses that no conflict of interests exists.

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