Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Abstract

Peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1␣ in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1␣ expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31 P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1␣ in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an Ϸ60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1␣ expression on whole-body energy expenditure, and PGC-1␣ transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKC , decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.diacylglycerol ͉ fatty acid oxidation ͉ insulin resistance ͉ magnetic resonance spectroscopy ͉ mitochondria

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…A greater transfection efficiency requires higher electroporation voltages, which induce muscle damage (C. R. Benton and A. Bonen, unpublished data) [20]. Compared with transgenic Pgc-1α animals, transfection of a single muscle with Pgc-1α offers several advantages: (1) it is possible to examine PGC-1α-induced metabolic regulation in a controlled manner, in vivo; (2) this can be done without disturbing whole-body fuel homeostasis; (3) the animal serves as its own control; and (4) the resulting phenotype is not unusual, as is the case in Pgc-1α transgenic mice [10,11,36].…”

“…However, experimental studies in vivo have been disappointing. Transgenic Pgc-1α (also known as Ppargc1a) overexpression yielded an insulin-resistant phenotype [10,11], calling into question the therapeutic potential of PGC-1α. Alternatively, a model of transgenic Pgc-1α overexpression may have obscured the positive metabolic effects of this co-activator.…”

“…In transgenic animals, Pgc-1α mRNA overexpression is very large (6-to 21-fold increase) [10][11][12], well beyond that which occurs physiologically [13]. Excessive PGC-1α production induces many undesirable consequences, including abnormal mitochondrial proliferation, disruption of myofibrillar architecture, displacement of nuclei [12], obesity, intramuscular lipid accumulation and insulin resistance [10,11].…”

“…Excessive PGC-1α production induces many undesirable consequences, including abnormal mitochondrial proliferation, disruption of myofibrillar architecture, displacement of nuclei [12], obesity, intramuscular lipid accumulation and insulin resistance [10,11]. We [3,13] have suggested that insulin resistance in PGC-1α transgenic mice [10,11] may stem from a large, PGC-1α-induced increase in the fatty acid transporter, fatty acid translocase (FAT), which has been associated with increases in intramuscular lipids and insulin resistance in humans and in animals [14,15]. Viewed in this light, PGC-1α-induced insulin resistance in transgenic mice is less of a paradox than has been suggested [11].…”

“…We [3,13] have suggested that insulin resistance in PGC-1α transgenic mice [10,11] may stem from a large, PGC-1α-induced increase in the fatty acid transporter, fatty acid translocase (FAT), which has been associated with increases in intramuscular lipids and insulin resistance in humans and in animals [14,15]. Viewed in this light, PGC-1α-induced insulin resistance in transgenic mice is less of a paradox than has been suggested [11]. Recently, we showed that inducing a modest increase in PGC-1α protein, based on physiological and metabolic considerations, has an insulin-sensitising effect in healthy muscle [3].…”