title: Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation.
abstract: Obesity-induced insulin resistance is associated with both ectopic lipid deposition and chronic, low-grade adipose tissue inflammation. Despite their excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This has raised the question of whether burning off the excess fat could improve the obese metabolic phenotype. Here we used human-safe nonimmunoreactive adeno-associated viruses (AAV) to mediate long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid β-oxidation, or its permanently active mutant form CPT1AM, to high-fat diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater extent, CPT1AM-expressing mice showed an enhanced hepatic FAO which resulted in increased production of CO(2) , adenosine triphosphate, and ketone bodies. Notably, the increase in hepatic FAO not only reduced liver triacylglyceride content, inflammation, and reactive oxygen species levels but also systemically affected a decrease in epididymal adipose tissue weight and inflammation and improved insulin signaling in liver, adipose tissue, and muscle. 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, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Orellana-Gavaldà
authors.forename: Laura
authors.initials: L
authors.lastname: Herrero
authors.forename: Maria Ida
authors.initials: MI
authors.lastname: Malandrino
authors.forename: Astrid
authors.initials: A
authors.lastname: Pañeda
authors.forename: Maria
authors.initials: M
authors.lastname: Sol Rodríguez-Peña
authors.forename: Harald
authors.initials: H
authors.lastname: Petry
authors.forename: Guillermina
authors.initials: G
authors.lastname: Asins
authors.forename: Sander
authors.initials: S
authors.lastname: Van Deventer
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000008:administration & dosage* / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D003920:Diabetes Mellitus / Q000628:therapy*; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000628:therapy; D015316:Genetic Therapy; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000628:therapy*; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; D002334:Carnitine O-Palmitoyltransferase