Inhibition of ghrelin activity by the receptor antagonist [D-Lys3]-GHRP-6 enhances hepatic fatty acid oxidation and gluconeogenesis in a growing pig model

Despite its central role in regulating energy intake and metabolism, ghrelin is little understood when it comes to its effects on hepatic lipid and glucose metabolism. Growing pigs were intravenously injected with ghrelin receptor antagonist [D-Lys3]-GHRP-6 (DLys; 6 mg/kg body weight) for seven days to determine whether ghrelin plays a role in glucose and lipid metabolism. DLys treatment significantly reduced body weight gain and adipose histopathology found that DLys treatment dramatically reduced adipocyte size. DLys treatment significantly increased serum NEFA and insulin levels, hepatic glucose level and HOMA-IR, and significantly decreased serum TBA level of growing pigs after fasting. Moreover, DLys treatment changed the dynamics of serum metabolic parameters, including glucose, NEFA, TBA, insulin, GH, leptin, and cortisol. Liver transcriptome showed that DLys treatment affected the metabolism-related pathways. Compared with the control group, adipose tissue lipolysis (the adipose triglyceride lipase level was significantly increased), hepatic gluconeogenesis (the G6PC protein level was significantly increased) and fatty acid oxidation (the CPT1A protein level was significantly increased) were promoted in the DLys group. DLys treatment expanded degrees of oxidative phosphorylation in the liver, coming about in a higher NAD+ /NADH proportion and enactment of the SIRT1 signaling pathway. Additionally, the liver protein levels of the DLys group were significantly higher than those of the control group for GHSR, PPAR alpha, and PGC-1. To summarize, inhibition of ghrelin activity can significantly affect metabolism and alter energy levels by enhancing fat mobilization, hepatic fatty acid oxidation and gluconeogenesis without affecting fatty acid uptake and synthesis in the liver.