Selective Colocalization of GHSR and GLP-1R in a Subset of Hypothalamic Neurons and Their Functional Interaction

AGUGGIA, JULIETA; FERNANDEZ, GIMENA; CASSANO, DANIELA; MUSTAFÁ, EMILIO R; RODRÍGUEZ, SILVIA S; CANTEL, SONIA; FEHRENTZ, JEAN-ALAIN; RAINGO, JESICA; SCHIÖTH, HELGI B; HABIB, ABDELLA M; DE FRANCESCO, PABLO N; PERELLO, MARIO

Endocrinology

Endocrine Society

Año: 2024 vol. 166

The GH secretagogue receptor (GHSR) and the glucagon-like peptide-1 receptor (GLP-1R) are G protein-coupled receptors with critical, yet opposite, roles in regulating energy balance. Interestingly, these receptors are expressed in overlapping brain regions. However, the extent to which they target the same neurons and engage in molecular crosstalk remains unclear. To explore the potential colocalization of GHSR and GLP-1R in specific neurons, we performed detailed mapping of cells positive for both receptors using GHSR-eGFP reporter mice or wild-type mice infused with fluorescent ghrelin, alongside an anti-GLP-1R antibody. We found that GHSR+ and GLP-1R+ cells are largely segregated in the mouse brain. The highest overlap was observed in the hypothalamic arcuate nucleus, where 15% to 20% of GHSR+ cells were also GLP-1R+ cells. Additionally, we examined RNA-sequencing datasets from mouse and human brains to assess the fraction and distribution of neurons expressing both receptors, finding that double-positive Ghsr+/Glp1r+ cells are highly segregated, with a small subset of double-positive Ghsr+/Glp1r+ cells representing