FNDC5-knock out induces skeletal muscle and liver metabolic disorders in mice, especially in mice with high fat diet

Introduction It has been proved that FNDC5 plays a significant role in energy metabolism, myocardial protection and insulin sensitivity. However, the specific role and underlying pathways of FNDC5 in energy metabolism, including glucose and lipid metabolism and amino acid metabolism are unclear so far. Objectives This study objectives were to investigate the metabolic consequences of FDNC5 knockout in mouse muscle and liver tissue. Methods Wildtype (WT) and KO mice were fed either normal or high fat diets (HFD), and then global biochemical profiles were determined in gastrocnemius muscle and liver, which aims to examine possible interactions between FDNC5 function and dietary composition. Results Knockout of the FDNC5 gene resulted in a substantial number of metabolite differences, relative to WT in both muscle and liver. Metabolic differences between KO and WT tissues were much more predominant in the high fat diet mice. The data suggest decreased utilization of glucose for glycolysis in HFD KO muscle, along with a possible increase in glycogen synthesis. Glycolysis might be reduced in HFD KO muscle. Most amino acids were elevated in HFD FNDC5 KO muscle. FNDC5 KO raised the levels of liver glucose 6-phosphate and phosphoenolpyruvate, relative to WT, under HFD condition. Glycogen degradation may be reduced in FNDC5 KO livers. FNDC5 KO reduced succinate and increases fumarate under HFD conditions. Liver amino acid levels were elevated in HFD FNDC5 KO livers relative to HFD WT. Conclusion Metabolomic profiling revealed numerous changes to muscle and liver metabolites that suggest broad-ranging effects of FNDC5 on tissue metabolism. The data suggests a number of metabolic pathways to explore further.