Ghsr, the growth hormone secretagogue receptor, is a key receptor for the orexigenic peptide ghrelin. It plays a crucial role in multiple physiological processes such as feeding behavior, energy homeostasis, and glucose and lipid metabolism. It is highly expressed in the mesolimbic dopaminergic systems and the central nervous system, and its activation can trigger various signaling pathways like cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK [1,2,4].

In Parkinson's disease (PD) model, Ghsr knockout (Ghsr-/-) mice showed aggravated dopaminergic neurons degeneration due to compromised autophagy caused by lysosomal dysfunction. DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr-/-mice, enhancing autophagy initiation but with abnormal lysosomal function, ultimately exacerbating nigral dopaminergic neurons injury [3]. In diet-induced obesity (DIO) studies, global Ghsr-KO male rats were protected against DIO with decreased food intake, increased thermogenesis, and modified brain glucose metabolism, while female rats did not show the same effects [5]. Also, in male mice, deletion of Ghsr in a subset of GABA neurons led to failure in ghrelin-induced food intake, yet food deprivation-induced refeeding was higher in these mice compared to Ghsr-deficient mice, suggesting a ghrelin-independent role of Ghsr in these neurons for compensatory hyperphagia [6].

In conclusion, Ghsr plays essential roles in regulating feeding behavior, energy metabolism, and autophagy. Ghsr KO mouse models have provided valuable insights into its functions in diseases like PD and DIO, highlighting its potential as a therapeutic target for these and other related conditions [3,5,6].