The GLP-1 receptor agonist GL0034 activates central regions controlling glucose homeostasis and feeding behaviour

Background: GL0034 is a novel glucagon-like peptide-1 receptor (GLP-1R) agonist showing glucose-lowering effects with increased insulin and C-peptide levels, reduced plasma glucagon levels, long-term reduction in HbA1C, and reduced body weight when tested in type 2 diabetic mice. At equivalent doses, these effects were significantly higher than those obtained with other GLP-1R agonists used clinically. We evaluated whether GL0034 administration activated brain regions involved in the control of energy homeostasis, which could explain the beneficial effects of this agonist. Methods: C57BL/6 mice received SC injections of saline, GL0034 (12 or 24 nmol/kg), or semaglutide (12 or 24 nmol/kg). The mice were euthanized 2 hours after dosing and their brains were fixed with paraformaldehyde. Cryosections were prepared from the entire brain; c-fos expression was assessed by immunohistochemistry. Results: We observed induction of c-fos expression in response to GL0034 SC injections in the area postrema and the nucleus tractus solitarius of the dorsal vagal complex and in the parabrachial nucleus and locus coeruleus. Lower levels of c-fos expression were detected in the central amygdala, subfornical organ, vascular organ of the lamina terminalis, and ventromedial preoptic nucleus. No significant staining could be observed in the hypothalamus, including the arcuate nucleus and the dorsomedial hypothalamus. These results were qualitatively comparable after GL0034 and semaglutide SC injections. Conclusion: These results indicate that SC injection of GL0034 activates several central brain regions, which control energy homeostasis through regulation of autonomic nervous activity and feeding behavior, potentially impacting food preference and motivated feeding behavior. These central effects may combine with the direct stimulation of pancreatic beta cells and insulin secretion by GL0034 to ensure efficient control of glucose homeostasis. Disclosure A. Picard: None. D. Tarussio: None. R. Thennati: None. V.S. Burade: Employee; Self; Sun Pharmaceutical Industries Ltd. B. Thorens: Other Relationship; Self; Servier.