Obesity-induced weight gain, increase in fasting blood glucose and insulin levels, and augmented expression of gluconeogenic genes were restored to normal only 3 months after AAV treatment. Thus, CPT1A- and, to a greater extent, BMS-907351 CPT1AM-expressing mice were protected against obesity-induced weight gain, hepatic steatosis, diabetes, and obesity-induced insulin resistance. In addition, genetically
obese db/db mice that expressed CPT1AM showed reduced glucose and insulin levels and liver steatosis. Conclusion: A chronic increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be a potential molecular therapy for obesity and diabetes. (HEPATOLOGY 2011) Obesity is a major risk factor for disorders ranging from insulin resistance and type 2 diabetes (T2D) to hepatic
steatosis and cardiovascular disease. The incidence of obesity is increasing worldwide and a concerted effort is being made to understand its pathogenesis. Two main mechanisms have been proposed to explain obesity-induced insulin resistance: on the one hand the ectopic deposition of triacylglyceride (TAG) outside the adipose tissue,1 and on the other, check details the heightened inflammatory state of the adipose tissue and liver.2 However, the ultimate cause of obesity is an energy imbalance between intake and expenditure, leading to the accumulation of excess nutrients in lipid deposits. Therefore, any strategy able to tilt the balance towards fatty-acid oxidation (FAO) could improve obesity-induced disorders. Malonyl-CoA, derived from glucose metabolism and the first intermediate in lipogenesis, regulates FAO by inhibiting carnitine palmitoyltransferase 1 (CPT1). This makes CPT1 the rate-limiting step in mitochondrial fatty-acid β-oxidation. Short-term genetic studies that increased FAO in liver showed a decrease in hepatic TAG content3 and insulin resistance in obese rodents.4, Mannose-binding protein-associated serine protease 5 However, to date there is no successful approach to chronically increase FAO and improve whole-animal obesity-induced insulin resistance in vivo. Here we achieved hepatic gene transfer of CPT1A (CPT1
liver isoform) to obese mice by injecting adeno-associated viruses (AAV) into the tail vein. This led to a nonimmunoreactive, long-term increase in lipid oxidation. We also used a mutant but active form of CPT1A (CPT1AM6), which is insensitive to malonyl-CoA and therefore leads to a permanent increase in the rate of FAO, independently of the glucose-derived malonyl-CoA levels. Our results show that an increase in hepatic FAO through AAV-mediated gene transfer of CPT1A and CPT1AM reduced obesity-induced hepatic steatosis, weight gain, inflammation, diabetes, and insulin resistance in mice consuming a high-fat diet (HFD). Furthermore, CPT1AM expression also reduced glucose and insulin levels, and liver steatosis in genetically obese db/db mice.