Hypothalamic GABAergic Neurons Expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) Are Sensitive to Metabolic Status and Liraglutide in Male Mice

Abstract

<b><i>Introduction:</i></b> Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing <i>Cellular retinoic acid binding protein 1</i> (<i>Crabp1</i>). <b><i>Methods:</i></b> Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of <i>Crabp1</i> across the mouse brain and characterized the molecular identity of <i>Crabp1</i>^ARC neurons. We also determined whether <i>Crabp1</i>^ARC neurons are sensitive to fasting, leptin, and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. <b><i>Results:</i></b> <i>Crabp1</i>^ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and are distinct from the prototypical melanocortin neurons. <i>Crabp1</i>^<i>ARC</i> neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing <i>Htr3b</i>, <i>Tbx19</i>, and <i>Tmem215</i>. Notably, <i>Crabp1</i>^ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. <b><i>Conclusion:</i></b> <i>Crabp1</i>^ARC neurons represent a novel heterogeneous population of GABAergic neurons sensitive to metabolic status.