Abstract
Anorexia Nervosa (AN) is a complex disease that impairs the metabolic, mental and physiological health of affected individuals in a severe and sometimes lethal way. Many of the common symptoms in AN patients, such as reduced food intake, anxiety, impaired gut motility or overexercising are connected to both the orexigenic gut hormone ghrelin and the dopaminergic system. Targeting the ghrelin receptor (GhrR) to treat AN seems a promising possibility in current research. However, GhrR signaling is highly complex. First, the GhrR can activate four known intracellular pathways Gαq, Gαi/o, Gα12/13 and the recruitment of β-arrestin. Biased signaling provides the possibility to activate or inhibit only one or a subset of the intracellular pathways of a pleiotropic receptor. This allows specific targeting of physiological functions without adverse effects. Currently little is known on how biased signaling could specifically modulate GhrR effects. Second, GhrR signaling has been shown to be interconnected with the dopaminergic system, particularly in the context of AN symptoms. This review highlights that a biased agonist for the GhrR may be a promising target for the treatment of AN, however extensive and systematic translational studies are still needed and the connection to the dopaminergic system has to be taken into account.
Highlights
Anorexia nervosa (AN) is a complicated disease that has both psychological and metabolic components
The ghrelin receptor (GhrR) is expressed in different tissues both peripherally, e.g. in the pituitary gland or pancreatic islets and centrally, most importantly for Anorexia Nervosa (AN) in brain regions related to food intake and anxiety behavior, such as the hypothalamus, the VTA and the amygdala [50, 58,59,60]
Contradictory, ghrelin knockout mice fed with a high-fat diet (HFD) had an increase in energy expenditure and locomotor activity compared to wild type mice, which indicates a different effect of ghrelin and GhrR signaling depending on the metabolic state [103]
Summary
Anorexia nervosa (AN) is a complicated disease that has both psychological and metabolic components. The GhrR signaling in the central nervous system is closely related to the DAergic mesocorticolimbic system, which itself is often discussed in the context of AN [3, 7]. How to exploit this connection in order to target the disease with for instance a ghrelin receptor (GhrR). Biased Ghrelin Signaling Anorexia Nervosa agonist is still not well studied and has led to unsatisfying/ inconclusive results so far [3]. In order to target the central symptoms of AN with a biased GhrR agonist, it is necessary to understand the physiological function of all the GhrR signaling pathways in the context of AN
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