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Review
. 2017 Jan 27;8:10.
doi: 10.3389/fendo.2017.00010. eCollection 2017.

Ghrelin-Reactive Immunoglobulins in Conditions of Altered Appetite and Energy Balance

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Free PMC article
Review

Ghrelin-Reactive Immunoglobulins in Conditions of Altered Appetite and Energy Balance

Sergueï O Fetissov et al. Front Endocrinol (Lausanne). .
Free PMC article

Abstract

Part of circulating ghrelin is bound to immunoglobulins (Ig) protecting it from degradation and preserving its functional activity. This review summarizes the data on ghrelin- and desacyl-ghrelin-reactive IgG in conditions of altered appetite and energy balance. Plasma levels and affinity kinetics of such IgG were compared in patients with obesity and anorexia nervosa (AN) and in animal models of obesity including ob/ob mice, high-fat diet-induced obese mice, and obese Zucker rats as well as in mice after chronic food restriction and activity-based anorexia and in rats with methotrexate-induced anorexia. We show that plasmatic IgG in both obese humans and animals are characterized by increased affinity for ghrelin. In contrast, patients with AN and anorectic rodents all show lower affinity of ghrelin- and desacyl-ghrelin-reactive IgG, respectively, the changes which were not observed in non-anorectic, chronically starved mice. We also show that affinity of ghrelin-reactive IgG correlate with plasma levels of ghrelin. These data point to common mechanisms underlying modifications of affinity kinetics properties of ghrelin-reactive IgG during chronic alterations of energy balance in humans and rodents and support a functional role of such autoantibodies in ghrelin-mediated regulation of appetite.

Keywords: anorexia; autoantibodies; desacyl-ghrelin; ghrelin; obesity.

Figures

Figure 1
Figure 1
Relative to control (Ctrl) values (1.0) changes in plasma ghrelin and desacyl ghrelin as well as affinity of their reactive IgG in patients and animal models of obesity and anorexia. Changes in plasma levels of acyl-ghrelin (A) and desacyl-ghrelin (C). Changes in affinity (dissociation equilibrium constant, KD) of plasmatic IgG for acyl-ghrelin (B) and desacyl ghrelin (D). AN, anorexia nervosa patients; An, animal models of anorexia; OB, obese patients or animals. Mann–Whitney tests ***p < 0.001, **p < 0.01, and *p < 0.05.
Figure 2
Figure 2
Examples of correlations between affinity and levels of ghrelin-reactive IgG and plasma concentrations of acyl-ghrelin. Correlations between the values of dissociation equilibrium constants (KD) of plasmatic IgG reactive with ghrelin and acyl ghrelin in obese and anorectic patients and controls (A) and in ob/ob and lean mice (B). Correlations between plasma levels of ghrelin-reactive free IgG (C) as well as ratios of their free/total levels (D) in ob/ob and lean mice. Correlations between plasma levels of ghrelin-reactive total IgG in Zucker rats (E). R-squared and p-values for Pearson’s correlation tests are shown, **p < 0.01 and *p < 0.05.
Figure 3
Figure 3
A schematic model summarizing the postulated role of ghrelin-reactive IgG in ghrelin signaling in appetite control during normal and pathological conditions. According this model, acyl-ghrelin is protected by IgG from deacylation, therefore enhancing its orexigenic signaling to the brain. Changes in affinity of IgG for ghrelin in obese patients (increase) and in orexia nervosa patients (decrease) may enhance and diminish, respectively, ghrelin’s orexigenic effects. Desacyl-ghrelin may lower orexigenic effect via competing with ghrelin for ghrelin-reactive IgG resulting in increased ghrelin degradation. Moreover, decreased affinity of IgG for desacyl ghrelin may favor its dissociation from immune complexes and completion with ghrelin. The origin of changes in affinity of ghrelin- and desacyl ghrelin-reactive IgG is currently unknown but may potentially depend on antigenic stimulation from dysbiotic gut microbiota associated with long-term nutritional modifications in anorexia and obesity.

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