Brain Ghrelin Receptor Blockade Alleviates Fatty Liver Disease by Improving Brain Insulin Sensitivity

Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern, characterized by excessive fat accumulation in the liver and often linked to obesity and insulin resistance. While liver-centric treatments are common, emerging research highlights the crucial role of the central nervous system (CNS) in regulating metabolic homeostasis. This study investigates whether blocking ghrelin receptors specifically in the brain can improve NAFLD by enhancing hypothalamic insulin sensitivity.

Treatment with Compound GR-X significantly improved several key metabolic parameters in NAFLD mice. Liver triglyceride accumulation was markedly reduced by 43% (p<0.01) compared to vehicle-treated controls. Furthermore, the antagonist group exhibited a 35% improvement in glucose tolerance (p<0.05) and a 2.1-fold increase in hypothalamic p-AKT (a marker of insulin signaling activation) compared to controls. The most striking finding was a 43% reduction in hepatic triglyceride content, directly demonstrating the alleviation of NAFLD severity through central ghrelin receptor blockade. Inflammatory markers in the liver, such as TNF-α and IL-6, were also significantly decreased by 28% and 32% respectively (both p<0.05), indicating reduced hepatic inflammation. Body weight gain was attenuated by 15% (p<0.05) in the treated group, despite continued high-fat diet feeding.