A generic drug combination synergizes as exercise enhancers to ameliorate various metabolically-related diseases

To confirm if the combination of A and B therapy is beneficial for metabolic disease, we fed genetically obese Lepob/Lepob mice with a high fat, high fructose, high cholesterol diet ad libitum, to establish liver steatosis and moderate fibrosis in a way that faithfully recapitulates key features of human metabolic disease. And we performed gene expression analysis on muscle and liver from metabolic disease mice after treatment. 24 hours after drug treatment, the quadriceps muscle significantly upregulating gene signatures for innervation (NGF signaling), mitochondrial fatty acid oxidation (FAO) and vascularization (VEGF signaling). In the liver there was an increase in liver development genes and an increase in mitochondrial genes 24 hours after drug treatment. After 40 days of treatment, the drug treatment increased insulin-PI3K-mTOR signaling and neuromuscular Slit-Robo signaling, while decreasing extracellular matrix collagen production and fatty acid metabolism in muscles. The drug treatment increased anti-inflammatory signatures while decreasing lipogenesis signaling in the live. Taken together, our data showed that the liver is reversing steatosis and inflammation, and the muscle increased muscle insulin signaling sensitivity and function in metabolic disease after the drug treatment.