Relationship between plasma free fatty acids and uncoupling protein-3 gene expression in skeletal muscle of obese subjects: in vitro evidence of a causal link.
OBJECTIVE
To investigate whether skeletal muscle uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) gene expression is altered in massive obesity and whether it correlates with in vivo insulin sensitivity and with metabolic and hormonal status.


METHODS
Quantification of UCP2 and UCP3 gene expression in skeletal muscle of obese and lean subjects displaying different degrees of insulin sensitivity.


METHODS
Fourteen obese and 10 age- and sex-matched healthy control subjects with a mean body mass index (BMI) of 43.6 +/- 1.4 and 22.8 +/- 1.8 (+/- SEM), respectively.


METHODS
Insulin sensitivity by glucose clamp, body composition by bio-impedance, fasting plasma glucose, insulin, leptin and free fatty acids (FFA). Skeletal muscle UCP2 and UCP3 mRNA levels by quantitative reverse transcription polymerase chain reaction (RT-PCR).


RESULTS
No significant differences in UCP2 or UCP3 mRNA levels were found between obese and control subjects. No significant correlation was observed, in both groups, between UCP2 or UCP3 mRNA levels and both anthropometrical and metabolic parameters. In contrast, a highly significant correlation was observed between skeletal muscle UCP3, but not UCP2, mRNA levels and plasma FFA in the obese, but not in the lean, group. Furthermore, exposure of human myocytes to FFA for 24 h strongly induced both UCP3 and peroxisome proliferator-activated receptor-gamma (PPARgamma) but not UCP2 gene expression.


CONCLUSIONS
FFA levels correlate strongly with skeletal muscle UCP3 mRNA levels in obese, but not in lean, subjects; in addition, in human myocytes, high FFA concentrations promote UCP3 expression. Our studies therefore provide evidence that supports a role for increased plasma FFA concentrations in the regulation of human skeletal muscle UCP3 gene expression.
Sbraccia
Paolo
P
Loboratory of Molecular Medicine, Department of Internal Medicine, University of Rome 'Tor Vergata', Italy. sbraccia@med.uniroma2.it
D'Adamo
Monica
M
Leonetti
Frida
F
Buongiorno
Angela
A
Silecchia
Gianfranco
G
Basso
Maria Sole
MS
Tamburrano
Guido
G
Lauro
Davide
D
Federici
Massimo
M
Di Daniele
Nicola
N
Lauro
Renato
R
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000097:blood* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood; D007473:Ion Channels; D020738:Leptin / Q000097:blood; D016014:Linear Models; D008297:Male; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3