Nutrition and energy levels have an important impact on animal growth, production performance, disease occurrence and health recovery. Previous studies indicate that melanocortin 5 receptor (MC5R) is mainly involved in the regulations of exocrine gland function, lipid metabolism and immune response in animals. However, it is not clear how MC5R participates in the nutrition and energy metabolism of animals. To address this, the widely used animal models, including the overfeeding model and the fasting/refeeding model, could provide an effective tool. In this study, the expression ofMC5Rin goose liver was first determined in these models. Goose primary hepatocytes were then treated with nutrition/energy metabolism-related factors (glucose, oleic acid and thyroxine), which is followed by determination ofMC5Rgene expression. Moreover,MC5Rwas overexpressed in goose primary hepatocytes, followed by identification of differentially expressed genes (DEGs) and pathways subjected to MC5R regulation by transcriptome analysis. At last, some of the genes potentially regulated by MC5R were also identified in the in vivo and in vitro models, and were used to predict possible regulatory networks with PPI (protein–protein interaction networks) program. The data showed that both overfeeding and refeeding inhibited the expression ofMC5Rin goose liver, while fasting induced the expression ofMC5R. Glucose and oleic acid could induce the expression ofMC5Rin goose primary hepatocytes, whereas thyroxine could inhibit it. The overexpression ofMC5Rsignificantly affected the expression of 1381 genes, and the pathways enriched with the DEGs mainly include oxidative phosphorylation, focal adhesion, ECM–receptor interaction, glutathione metabolism and MAPK signaling pathway. Interestingly, some pathways are related to glycolipid metabolism, including oxidative phosphorylation, pyruvate metabolism, citrate cycle, etc. Using the in vivo and in vitro models, it was demonstrated that the expression of some DEGs, includingACSL1,PSPH,HMGCS1,CPT1A,PACSIN2,IGFBP3,NMRK1,GYS2,ECI2,NDRG1,CDK9,FBXO25,SLC25A25,USP25andAHCY, was associated with the expression ofMC5R, suggesting these genes may mediate the biological role of MC5R in these models. In addition, PPI analysis suggests that the selected downstream genes, includingGYS2,ECI2,PSPH,CPT1A,ACSL1,HMGCS1,USP25andNDRG1, participate in the protein–protein interaction network regulated byMC5R. In conclusion, MC5R may mediate the biological effects caused by changes in nutrition and energy levels in goose hepatocytes through multiple pathways, including glycolipid-metabolism-related pathways.