Uncovering the Role of Gpr45 in Obesity Regulation

G protein-coupled receptors (GPCRs) are the most druggable targets in biology due to their cell-type specificity, ligand binding, and cell surface accessibility. Underscoring this, agonists for GPCRs have recently revolutionized the treatment of diabetes and obesity. The rampant success of these compounds has invigorated interest in identifying additional GPCRs that modulate appetite and body weight homeostasis. One such potential therapeutic target is G-protein couped receptor 45 (Gpr45), an orphan GPCR expressed both centrally and peripherally. We aimed to explore the role of Gpr45 as well as neurons expressing Gpr45 in energy balance. Three novel transgenic mouse models were engineered to investigate the functional contribution of Gpr45 to body weight and appetite regulation: 1) a global Gpr45 knockout, 2) a conditional floxed Gpr45 allele, and 3) a Gpr45-CreERT2 knock-in. Metabolic profiling was performed in global Gpr45 knockout animals including body weight, food intake, body mass, energy expenditure, and body temperature measurements. Animals harboring a conditional floxed Gpr45 allele were bred to mice expressing Cre-recombinase in excitatory neurons labeled via Vesicular glutamate transporter 2 (Vglut2), inhibitory cells expressing Vesicular GABA transporter (Vgat), or neurons marked by the transcription factor Single-minded 1 (Sim1) and monitored for body weight and food consumption. Additionally, floxed Gpr45 mice were bilaterally injected with AAV-Cre targeting the paraventricular nucleus of the hypothalamus (PVH) and body weight and food intake were evaluated. The Gpr45-CreERT2 knock-in model was used to express chronic and acute actuators to the PVH to assess the role of PVHGpr45 neurons in energy homeostasis. Global Gpr45 disruption caused marked weight gain, increased food intake and fat mass, but no detectable alterations in core temperature or energy output. Selective deletion of Gpr45 from Sim1+ or excitatory Vglut2+ but not inhibitory Vgat+, neurons produced obesity and hyperphagia. Targeted deletion of Gpr45 from the PVH phenocopies these metabolic changes suggesting a major site of action of Gpr45 signaling is glutamatergic neurons residing in the PVH. Tetanus toxin light chain (TeNT) was used to permanently silence PVHGpr45 neuronal activity in Gpr45-CreER mice leading to rapid weight accumulation and escalated food intake. These experiments highlight the critical role of both Gpr45 signaling and neural network activity in the regulation of body weight and appetite. A mutated version of the bacterial sodium channel, NaChBac, was used to constitutively activate PVHGpr45 neuronal activity in Gpr45-CreER mice with limited to no effect on body weight and food consumption, implicating redundant circuitry acting in concert to bias weight loss protection. Acute chemogenetic stimulation of PVHGpr45 neurons durably suppressed food intake regardless of caloric need state or food palatability demonstrating the capacity of these cells to curb appetite. Gpr45 is a putative therapeutic candidate that could be targeted to combat obesity and overeating.