Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders

Abstract

Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders.

Plasma Peptide Concentrations and Peptide-Reactive Immunoglobulins in Patients with Eating Disorders at Inclusion in the French EDILS Cohort (Eating Disorders Inventory and Longitudinal Survey)

“…In the present study, we observed no significant difference in the anti-α-MSH IgG concentrations and their affinity among the three groups. This is in agreement with another report from our group comparing anti-MSH IgG concentrations among AN, BN, and BED (DSM-IV) patients [48]. It is worth discussing if some bacterial signaling molecules may contribute to the induction of satiety in a way that is similar to endogenous α-MSH.…”

Host Starvation and Female Sex Influence Enterobacterial ClpB Production: A Possible Link to the Etiology of Eating Disorders

“…In fact, after an increase of ClpB expression during starvation, the immune system in females is already sensitized for the ClpB antigen to raise an adaptive antibody response, as expressed in the increased production of anti-ClpB IgG. While such IgG are not pathogenic themselves, their cross-reactivity with α-MSH may lead to an increased production of immune complexes, with α-MSH overactivating the MC4R and resulting in increased satiety and anxiety of ED patients [9]. In the present study, an increased α-MSH-reactive IgM and IgG response to starvation was found in both sexes, but it was more pronounced in females.…”

“…The clinical relevance of α-MSH-reactive immunoglobulin (Ig)M and IgG antibodies to EDs was supported by correlations of their plasma levels with psychopathological traits in both AN and BN patients [8]. The mechanism of action of α-MSH-reactive IgG may include activation of MC4R by the immune complexes with α-MSH, which deregulates feeding behavior and emotions [9].…”

Changes in Microbiota and Bacterial Protein Caseinolytic Peptidase B During Food Restriction in Mice: Relevance for the Onset and Perpetuation of Anorexia Nervosa

“…Moreover, a recent study showed that the levels of α-MSH-reactive IgG, the binding of melanocortin 4 receptor (MC4R) and the cellular internalization rate of MC4R-expressing cells were all lower in obese subjects [26]. Inverse results were found in anorexic and bulimic patients [26]. Other studies also confirmed the implication of α-MSH reactive Ig in the physiological regulation of feeding and mood [27].…”

“…This suggests that α-MSH reactive Ig may interfere with melanocortin signaling in both normal and pathological conditions. Moreover, a recent study showed that the levels of α-MSH-reactive IgG, the binding of melanocortin 4 receptor (MC4R) and the cellular internalization rate of MC4R-expressing cells were all lower in obese subjects [26]. Inverse results were found in anorexic and bulimic patients [26].…”