title: Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities.
abstract: An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [(11)C]palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI ≥/< 30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [(11)C]palmitate and [(18)F]fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P < 0.05) in skeletal muscle. FA esterification was reduced by ~70% in SAT (P < 0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P < 0.05). Trimetazidine increased skeletal muscle FA esterification (P < 0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle.
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Marco
authors.initials: M
authors.lastname: Bucci
authors.forename: Ronald
authors.initials: R
authors.lastname: Borra
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.forename: Romina
authors.initials: R
authors.lastname: Maggio
authors.forename: Helena
authors.initials: H
authors.lastname: Tuunanen
authors.forename: Vesa
authors.initials: V
authors.lastname: Oikonen
authors.forename: Silvia
authors.initials: S
authors.lastname: Del Ry
authors.forename: Tapio
authors.initials: T
authors.lastname: Viljanen
authors.forename: Markku
authors.initials: M
authors.lastname: Taittonen
authors.forename: Sara
authors.initials: S
authors.lastname: Rigazio
authors.forename: Daniela
authors.initials: D
authors.lastname: Giannessi
authors.forename: Riitta
authors.initials: R
authors.lastname: Parkkola
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nuutila
authors.forename: Patricia
authors.initials: P
authors.lastname: Iozzo
mesh_terms: D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D005223:Fats / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D049268:Positron-Emission Tomography; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019440:Anti-Obesity Agents; D005223:Fats; D005227:Fatty Acids; D014665:Vasodilator Agents; D019788:Fluorodeoxyglucose F18; D014292:Trimetazidine