Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats.
OBJECTIVE
Reductions in peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) levels have been associated with the skeletal muscle insulin resistance. However, in vivo, the therapeutic potential of PGC-1alpha has met with failure, as supra-physiological overexpression of PGC-1alpha induced insulin resistance, due to fatty acid translocase (FAT)-mediated lipid accumulation. Based on physiological and metabolic considerations, we hypothesised that a modest increase in PGC-1alpha levels would limit FAT upregulation and improve lipid metabolism and insulin sensitivity, although these effects may differ in lean and insulin-resistant muscle.


METHODS
Pgc-1alpha was transfected into lean and obese Zucker rat muscles. Two weeks later we examined mitochondrial biogenesis, intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), GLUT4 and FAT levels, insulin-stimulated glucose transport and signalling protein phosphorylation (thymoma viral proto-oncogene 2 [Akt2], Akt substrate of 160 kDa [AS160]), and fatty acid oxidation in subsarcolemmal and intermyofibrillar mitochondria.


RESULTS
Electrotransfection yielded physiologically relevant increases in Pgc-1alpha (also known as Ppargc1a) mRNA and protein ( approximately 25%) in lean and obese muscle. This induced mitochondrial biogenesis, and increased FAT and GLUT4 levels, insulin-stimulated glucose transport, and Akt2 and AS160 phosphorylation in lean and obese animals, while bioactive intramuscular lipids were only reduced in obese muscle. Concurrently, PGC-1alpha increased palmitate oxidation in subsarcolemmal, but not in intermyofibrillar mitochondria, in both groups. In obese compared with lean animals, the PGC-1alpha-induced improvement in insulin-stimulated glucose transport was smaller, but intramuscular lipid reduction was greater.


CONCLUSIONS
Increases in PGC-1alpha levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulin-resistant muscle. These positive effects are probably attributable to limiting the PGC-1alpha-induced increase in FAT, thereby preventing bioactive lipid accumulation as has occurred in transgenic PGC-1alpha animals.
Benton
C R
CR
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
Holloway
G P
GP
Han
X-X
XX
Yoshida
Y
Y
Snook
L A
LA
Lally
J
J
Glatz
J F C
JF
Luiken
J J F P
JJ
Chabowski
A
A
Bonen
A
A
D000818:Animals; D015153:Blotting, Western; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D013851:Thinness / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; C000715470:MAS1 protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D005947:Glucose