High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle
Introduction
Physical exercise has profound effects on glucose metabolism in contracting skeletal muscle. Exercise activates glucose transport (GT) in skeletal muscle by inducing translocation of glucose transporter 4 (GLUT4) to the cell surface by insulin-independent and insulin-dependent mechanisms (reviewed in Hayashi et al [1]). The activity of insulin-independent GT is markedly enhanced during exercise; and this effect wears off within several hours after exercise, when the postexercise increase in insulin sensitivity that leads to insulin-dependent GT becomes prominent. Wallberg-Henriksson et al [2] showed in isolated rat skeletal muscle that the rate of insulin-independent GT is maximal immediately after exercise, whereas the postexercise increase in insulin sensitivity becomes detectable 3 hours after exercise. Correspondingly, Price et al [3] showed in human muscle that postexercise glycogen repletion occurs in an insulin-independent manner for about 1 hour after exercise, after which insulin-dependent glycogen repletion becomes significant. These exercise-stimulated mechanisms form the basis of practices to prevent individuals from developing glucose intolerance and to improve glycemic control in patients with type 2 diabetes mellitus.
It is of interest to know whether exercise-stimulated GT, including both the insulin-independent and insulin-dependent components, is normal in the state of insulin resistance. Although numerous studies have shown that a high-fat diet (HFD) causes insulin resistance in muscles at rest, it is unknown whether an HFD interferes with the short-term stimulatory effect of exercise on insulin sensitivity. Only one study has addressed this topic and demonstrated that the postexercise increase in muscle insulin sensitivity is abolished completely in HFD-fed rats [4]. In that study, however, insulin-dependent GT was measured before the insulin-independent glucose uptake wore off (its activity was still 160% higher than the basal uptake), indicating that the net effect of exercise on insulin sensitivity was substantially underestimated because of residual glucose uptake activity. There is considerable controversy over whether an HFD alters the effects of short-term exercise on insulin-independent GT. Most investigators have reported about 50% reduction in the rate of muscle GT stimulated by exercise [5], [6], [7] and electrical stimulation [6], [8], [9] in HFD-fed rodents, although others did not find these effects [4], [10]. Moreover, some studies have shown that the reduction in insulin-independent GT was not associated with decreased muscle GLUT4 content [5], [6]; but a conflicting result was also reported [8]. Although Hansen et al [9] showed that impairment of the exercise-stimulated GT is associated with decreased GLUT4 translocation to the cell surface, the responsible signaling mechanism remains to be elucidated.
The purposes of our present study were to determine how HFD affects insulin-independent and insulin-dependent GT activated by a single bout of endurance exercise and to explore the underlying mechanism that leads to the change in exercise-stimulated glucose utilization. We found that both components of exercise-induced GT were impaired by an HFD and that these changes were accompanied by a decrease in 5′adenosine monophosphate (AMP)–activated protein kinase (AMPK) activation in skeletal muscle of rats fed an HFD for 4 weeks.
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Animals and diets
Male Wistar rats at the time of weaning were purchased from Clea Japan (Tokyo, Japan). Animals were fed either control diet (CD) (MF; 3.6 kcal/g, 12% kcal fat, source: soybean; Oriental Yeast, Tokyo, Japan) or HFD (D12493; 5.2 kcal/g, 60% kcal fat, source: soybean/lard; Research Diets, New Brunswick, NJ) for 4 weeks. All animal experiments were approved by the Animal Research Committee, Graduate School of Medicine, Kyoto University.
Exercise and muscle sampling
The rats were accustomed to a rodent treadmill (Muromachi
Metabolic parameters in rats fed the CD and HFD
Table 1 summarizes the basic characteristics of the CD- and HFD-fed rats (Table 1). Rats fed the HFD for 4 weeks were slightly heavier and had higher plasma concentrations of glucose, insulin, triglycerides, and leptin than did CD-fed rats.
HFD increases IMCL in soleus
We analyzed the influence of HFD on IMCL concentration by ORO staining (Fig. 1A-B). Muscle fiber type was determined by myofibrillar ATPase histochemical staining (Fig. 1C-F). The fiber type proportions did not differ significantly between CD-fed and HFD-fed
Discussion
Endurance exercise has long been advocated as beneficial for patients with insulin resistance associated with type 2 diabetes mellitus and obesity. This is based partly on the observation that, even in people with insulin resistance, endurance exercise stimulates muscle glucose uptake in skeletal muscle by 2 distinct mechanisms: one insulin independent and one insulin dependent (reviewed in Hayashi et al [1]). Reversal of the short-term increase in GT after cessation of contractile activity is
Acknowledgments
We thank Takao Shirai, Kyoto University, for technical suggestions and Yoko Koyama and Kaoru Ijiri for secretarial assistance. We also thank the Radioisotope Research Center of Kyoto University for instrumental support in the radioisotope experiments. This work was supported by a research grant from the Japan Society for the Promotion of Science (to Tatsuya Hayashi). Taro Toyoda was supported by the Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.
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