Fig. 6: Hypothetical model of α-melanocyte-stimulating hormone (α-MSH)/IgG immune complex (IC) activation of melanocortin 4 receptor (MC4R) in healthy controls and patients with obesity or anorexia nervosa.

Plasmatic IgG transport α-MSH by forming IC that bind and activate MC4R. During interaction with the receptor, the C-terminal (Ct) of α-MSH should be presented by IgG enabling IC docking and binding. During binding, α-MSH dissociates from IC and its pharmacophore (Phar) enters the receptor binding pocket, resulting in receptor activation ex. cyclic adenosine monophosphate production. The α-MSH/IgG IC then internalized together with MC4R, resulting in temporal desensitization. As illustrated in Fig. 5f, in healthy subjects IgG bind mainly the central and the N-terminal parts of α-MSH making the C-terminal available for MC4R docking. However, in obese patients the C-terminal is hidden by IgG, preventing α-MSH/IgG IC docking to MC4R. In contrast, in anorexia nervosa (AN) patients, the C-terminal of α-MSH is not bound by IgG, favoring receptor recognition. The changes in α-MSH epitope binding in obesity combined with decreased dissociation of IC and low plasma levels of α-MSH-reactive IgG may cause deficient activation of MC4R, promoting positive energy balance. In contrast, the α-MSH epitope-binding properties of IgG in AN combined with increased dissociation of IC and increased plasma levels of α-MSH-reactive IgG are favorable for more efficient activation of MC4R by α-MSH/IgG IC, resulting in enhanced satiety signaling and negative energy balance