https://orcid.org/0000-0001-5425-1946
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María Paula Cornejo, Gimena Fernandez, Agustina Cabral, Franco Barrile, Florencia Heredia, Guadalupe García Romero, Juan Pablo Zubimendi Sampieri, Juan Ignacio Quelas, Sonia Cantel, Jean-Alain Fehrentz, Antonia Alonso, Ramon Pla, José Luis Ferran, María Florencia Andreoli, Pablo Nicolas De Francesco, Mario Perelló, GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice, Endocrinology, Volume 165, Issue 7, July 2024, bqae061, https://doi.org/10.1210/endocr/bqae061
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Abstract
The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)–producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)–expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation–induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.
