Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities

Abstract

Bucci M, Borra R, Någren K, Maggio R, Tuunanen H, Oikonen V, Del Ry S, Viljanen T, Taittonen M, Rigazio S, Giannessi D, Parkkola R, Knuuti J, Nuutila P, Iozzo P. Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities. Am J Physiol Endocrinol Metab 301: E105-E112, 2011. First published April 19, 2011 doi:10.1152/ajpendo.00680.2010.-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 Ն/Ͻ 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 Ͻ 0.05) in skeletal muscle. FA esterification was reduced by ϳ70% in SAT (P Ͻ 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 Ͻ 0.05). Trimetazidine increased skeletal muscle FA esterification (P Ͻ 0.01) and mildly upregulated glucose phosphorylation (P ϭ 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. fatty acid esterification; imaging AN IMPAIRED ABILITY TO STORE FATTY ACIDS (FA) in adipose tissue may be implicated in the pathogenesis of obesity related diseases, via overexposure of lean tissues to FA, leading to formation of toxic lipid metabolites and free radicals (17,22).Obesity is typically associated with derangements in FA metabolism and oxidation (FAO), but there is contrasting evidence as to whether FAO is increased or decreased (21) in skeletal muscle. One potential explanation is that (39) skeletal muscle FAO may initially increase to compensate for an augmented FA release from adipose tissue (12, 27), thus preventing the accumulation of intramyocellular lipids (32). Once this pathway becomes saturated, the build-up of intramyocellular triglycerides (12) and free radicals (34) may compromise mitochondrial function (6), resulting in a decline i...

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“…1 H-MRS spectra were analysed using the LCModel software package (version 2.6-1, www.s-provencher. com/pages/lcmodel.shtml) [9].…”

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