Obesity and type II diabetes are characterized by impaired glucose uptake and reduced fatty acid oxidation. Reduced fatty acids oxidation is known to cause insulin resistance, particularly in skeletal muscle^{8, 28}. Skeletal muscle is responsible for majority (>80%) of insulin-stimulated whole body glucose disposal, and hence, plays an important role in the pathogenesis of insulin resistance and diabetes²⁸. The genetically obese Zucker rat (fa/fa) is a well-characterized model of insulin resistant, exhibiting a range of metabolic abnormalities including hyperinsulinemia¹³.

The thiazolidinediones (TZDs) are known peroxisome proliferators-activated receptor (PPARs) agonists and major compounds for the treatment of type 2 diabetes. Rosiglitazone, a TZDs, improves skeletal muscle glucose uptake and insulin sensitivity through regulation of target genes^13,33. Recently, studies suggest that administration of TZD to obese animal models with insulin resistance and diabetes patients can lead to the improvement of glucose uptake and insulin sensitivity associated with increasing glucose transportor-4 (GLUT-4), AMP activated protein kinase (AMPK), and PPAR-γ coactivator-1α (PGC-1)^{13, 20}.

PPARs is a family of nuclear hormone receptors that include PPAR-α, -β/δ, and -γ subtypes of. It is activated by fatty acid metabolism and regulates whole body insulin sensitivity¹¹. PGC-1α provides a platform for the recruitment of regulatory protein complexes that exert powerful effects on gene transcription, particularly in regulation of PPARs expression^{2, 9}. Also, GLUT-4 and AMPK are cellular energy sensors that regulate glucose and lipid metabolism. The activation of GLUT-4 and AMPK changes many metabolic reactions that would be beneficial to type 2 diabetes and metabolic syndrome, including, increased glucose uptake and fatty oxidation in skeletal muscle²⁰. But recent studies show that they decrease expression of PPAR-α, -β/δ, -γ, PGC-1α, GLUT-4, and AMPK in the development of muscular insulin resistance ^{20, 27}.

Exercise training also induces several adaptations, such as promoting glucose uptake, insulin sensitivity and insulin signaling pathway in skeletal muscle. In addition, exercise training elevates GLUT-4, AMPK, PPAR-β/α, and PGC-1α activity ^{25, 31}.

The potential for exercise training and rosiglitazone to improve skeletal muscle insulin sensitivity by multiple mechanisms raises the possibility that these treatments may also produce additive effects. However, the mechanism by which these therapies increases glucose uptake and improve insulin sensitivity in skeletal muscle is still unclear. Accordingly, the present study was performed to examine the independent and interactive effects of exercise training and rosiglitazone treatment on the expression of PPAR-α, -β/δ, -γ, PGC-1α, GLUT-4 and p-AMPK in skeletal muscle of induced diabetic obese Zucker rats.

The major findings of the present study are that s streptozotocin-induced diabetic Zucker rats showed decreased body weight. Rosiglitazone treatment led to increased body weight. Plasma glucose level of the induced diabetic Zucker rats increased in all periods. Exercise training with rosiglitazone treatment significantly decreased the body weight and plasma glucose level. Also, exercise training and rosiglitazone treatment showed increased expression of PPAR-α, -β/δ, -γ, PGC-1α, adiponectin, GLUT-4, and p-AMPK-α2 in skeletal muscles, as compared with the induced diabetic Zucker rats. Particularly, combination treatment of exercise training and rosiglitazone showed activated expression of these molecules in skeletal muscles than exercise training and rosiglitazone alone. These results indicated that exercise training combined with rosiglitazone might have additive effects for the therapy of diabetes through the improvement of glucose uptake and insulin sensitivity in skeletal muscle.

Rosiglitazone is known to improve insulin sensitivity through the activation of PPARs¹¹. Despite its proven efficacy, widespread use of rosiglitazone for diabetes is limited by their propensity to promote weight gain^{10, 32}. In this study, a substantial weight gain was observed in subjects treated with rosiglitazone; however, exercise training combined with rosiglitazone treatment leads to controlled reduction of body weight. Also, plasma glucose levels were higher in induced diabetic Zucker rats than normal rats. Exercise training combined with rosiglitazone treatment resulted in significantly decreased plasma glucose level. These results suggested that combined therapy can minimize the side effects such as weight gain with rosiglitazone treatment and can positively ameliorate the hyperglycemia and enhanced glucose uptake and transport in skeletal muscle.

Obesity and type II diabetes showed excess lipid accumulation, reduced oxidative capacity of mitochondria and impaired glucose transport in skeletal muscle²⁸. The improvement of glucose transport and fatty acids oxidation are an important therapeutic goal in obesity and diabetes patients. Exercise training and rosiglitazone are two well-known treatments for improving glucose transport and fatty acids oxidation independently. Therefore, combination of exercise training with rosiglitazone could affect glucose transport and fatty acids oxidation in diabetic patients, which would be of therapeutic importance. To test this idea, we treated diabetic induced-obese Zucker rats with exercise training, rosiglitazone, and exercise training combined with rosiglitazone.

PPARs, PGC-1α and adiponectin are major factors involved in the improvement of insulin sensitivity and fatty acids oxidation in skeletal muscle. The PPAR-α, -β/δ, and PPAR-α isoforms are differentially expressed in tissues that have various functions in lipid metabolism and glucose homeostasis. PGC-1α regulates PPAR-target genes involved in fatty acid oxidation, as well genes involved in glucose transport¹⁷. Expression of PPAR-α, -β/γ, PPAR-α, and PGC-1α in skeletal muscle was significantly lower in the diabetic state. Reduced PPAR-α, -β/δ, -γ, PGC-1α, and PGC-1α in the diabetes state is followed by increased insulin tolerance and reduction of fatty oxidation in skeletal muscle^{25-27, 29} due to their in glucose transport to skeletal muscle and mitochondrial function of skeletal muscle. In the present study, the muscle expression of PPAR-α, -β/δ, -γ, and PGC-1 was reduced in induced diabetic rats; whereas, exercise training and rosiglitazone treatment increased expression of PPAR-α, -β/δ, -γ, and PGC-1α expression in muscles, as compared with normal and diabetic induced-rats. Increased levels of PPAR-α, -β/δ, -γ, and PGC-1α after exercise training and rosiglitazone treatment may be the result of improved insulin sensitivity and mitochondrial function. Particularly, the additive effects of combination therapy raises the possibility that exercise training with rosiglitazone treatment in diabetes patients could have substantial therapeutic effects to improve glucose transport and mitochondrial function. Also, Hevener et al (2000) reported additive effects of the combination of exercise and rosiglitazone treatment to improve insulin sensitization. We observed that combination therapy significantly increased the expression of PPAR-α, -β/δ, -γ, and PGC-1α expression in muscles. In the present study, expression of PPAR-α, -β/δ, -γ, and PGC-1α after combination therapy, may imply an amelioration of insulin resistance and improvement of mitochondrial function in skeletal muscle of obesity and diabetes.

Adiponectin is an adipose-derived peptide that plays an important role in glucose and lipid homeostasis both directly and as a modulator of insulin sensitivity³⁵. Adiponectin levels decrease in parallel with the development of insulin resistance and thus prior to the onset of diabetes^{14, 22}. Administration of adiponectin is accompanied by lower plasma glucose levels, as well as increased insulin sensitivity. Many studies have investigated the possible link between adiponectin level or adiponectin receptor (AdipoR) expression and the insulin-sensitizing actions of exercise and TZDs^{4, 34}. Bluher et al. (2006) demonstrated that 4weeks training in diabetic patients caused a significant increase in AdipoR and AMPK expression of skeletal muscle, which may mediate the adiponectin-stimulated fatty acids oxidation and glucose uptake. In this study, we showed that adiponectin expression in skeletal muscle was significantly decreased in induced diabetic Zucker rats, as compared with normal rats; whereas, exercise, rosiglitazone, and exercise combined with rosiglitazone treatment showed significant increases in adiponectin expression. These results indicated that exercise training combined with rosiglitazone is positively associated with improvement in glucose uptake and fatty acids oxidation via increased adiponectin expression.

GLUT-4 is an isoform of glucose family found primarily in insulin sensitive tissues. Insulin-stimulated glucose uptake occurs primarily via the translocation of GLUT-4 to the plasma membrane³. Previous studies showed that the decrease in GLUT-4 protein levels in skeletal muscle of diabetic obese rats plays a role in the level of insulin resistance³⁶. AMPK is a fuel sensing enzyme that is implicated in insulin sensitivity and lipid homeostasis. AMPK activation causes many metabolic changes including increased glucose uptake and metabolism by increasing GLUT-4 expression and increased oxidation of fatty acids. Therefore, AMPK expression would be beneficial to individuals with type 2 diabetes and metabolic syndrome¹². A recent study showed that AMPK activation is impaired in skeletal muscle from obese type 2 diabetics⁷. Our results likewise indicated that GLUT-4 and p-AMPK-α2 expression significantly decreases in muscles of induced diabetic rats, as compared with normal rats. These results are consistent with the possibility that a deficiency of GLUT-4 and p-AMPK-α2 expression contributes to decreased glucose transport and increased insulin resistance in diabetic obese rats, because activation of GLUT-4 and AMPK in skeletal muscle may enhance insulin-stimulated glucose transport and glycogen content and lead to increases in fat oxidation, induction of PGC-1α and genes governing mitochondrial biogenesis and enzymes of oxidation phosphorylation^{6, 13, 16, 18}. However, treatment with exercise, rosiglitazone, and exercise combined with rosiglitazone augment GLUT-4 and p-AMPK-α2 expression in skeletal muscle of diabetic obese rats.

In summary, exercise training and rosiglitazone treatment activated PPAR-α, -β/δ, -γ, PGC-1α, adiponectin, GLUT-4, and p-AMPK-α2 expression, which was associated with improvement of glucose transport and fatty acids oxidation. Furthermore, the combination of these two therapies led to essential improvement of insulin sensitivity in induced diabetic obese rats. Thus, combination therapy is potentially a key therapeutic strategy of diabetes.