Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa

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.

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

“…Thus, developing both new therapeutic approaches and a better understanding of diabetes pathophysiology is critical. An important clue may lie in recent evidence that dopamine (DA) signaling via DA D 2 -like receptors including D 2 receptors (D2R) are important regulators of metabolism ( Farino et al., 2020 ; Freyberg et al., 2017 ; Khelifa et al., 2021 ). Moreover, D2R polymorphisms are associated with insulin resistance and T2D ( Barnard et al., 2009 ).…”

Hypothalamic dopamine neuron activity is modulated by caloric states and amphetamine abuse in zebrafish larvae

“…Dopaminergic neurons receive synapses from various neuron populations in the brain (Watabe-uchida et al, 2012). One such neuron population is Agouti-related protein/Neuropeptide-Y (AgRP/NPY) neurons in the hypothalamus, which get stimulated when ghrelin (a gut hormone that is secreted during starvation) binds to its receptors on AgRP/NPY neuron surface (Essner et al, 2017; Khelifa et al, 2021). Food deprivation increases AgRP/NPY mRNA expression (Bi et al, 2003).…”

Modulation of locomotion and motor neuron response by the cohesive effect of acute and chronic feeding states and acute d-amphetamine treatment in zebrafish larvae

“…(Cummings et al, 2001; Tschöp et al, 2001; Stuber et al, 2002; Bi et al, 2003; Müller et al, 2015) Study shows the presence of ghrelin receptors in the AgRP neuron population and ghrelin binding on these receptors increases the excitability of AgRP neurons(Chen et al, 2017). This AgRP activation sends synapses to Dopaminergic neurons via the Lateral hypothalamus in rodents(Castro et al, 2015; Khelifa et al, 2021). Furthermore, ghrelin receptors are also present on dopaminergic neurons in the Ventral Tegmental Area (VTA) in rodents(Quarta et al, 2009; Jerlhag et al, 2010; Edvardsson et al, 2021).…”