Aerobic exercise's reversal of insulin resistance by activating AMPKα-ACC-CPT1 signaling in the skeletal muscle of C57BL/6 Mice

Journal Title (Medline/Pubmed accepted abbreviation): Int J Sport Nutr Exerc Metab
Year: 2010
Volume: 20
Page numbers: 370-380
doi (if applicable):

Summary of Background and Research Design

Background:Type 2 diabetes is a serious metabolic disease characterized by insulin resistance, variable insulin secretion, and hyperglycemia. The mechanism underlying the causes of type 2 diabetes involves the induction of insulin resistance by the interaction of various metabolic-related genes with environmental factors such as diet, obesity, exercise, stress, and age. Many studies suggest that regular exercise improves insulin signal activity in skeletal muscle, but the mechanism of this process is not completely clear. AMPK (AMP-activated protein kinase α) is an enzyme involved in glucose and lipid metabolism. It is generally believed that AMPKα signaling through the ACC (acetyl-CoA carboxylases)-malonyl CoA-CPT1 (carnitine palmitoyltransferase 1) pathway is an essential mechanism in regulation of fat oxidation in skeletal muscle, which has been recognized as a key modulator of insulin action. The discovery that AMPKα is activated by exercise in both rodents and humans provided a possible molecular mechanism underlying the beneficial effects of exercise on insulin resistance.

Hypothesis:The authors hypothesized that 6 weeks of treadmill exercise at 75% of maximal oxygen consumption (VO2max) would reverse the abnormalities of AMPKα-ACC-CPT1 signaling in insulin-resistant mice.

Subjects: 50 male, 8-week-old, wild-type, C57BL/6J mice

Experimental design:Randomized, controlled

Treatments and protocol: Mice were randomly divided into 2 groups and were fed with normal chow (n = 20) or a high-fat diet to produce insulin resistance (n = 30) for 8 weeks. The control group was randomly divided into normal-chow control group (NC, n = 10) and normal-chow exercise group (NE, n = 10). Twenty of 30 mice were confirmed insulin resistant and were randomly divided into a high-fat-diet control group (HC, n = 10) and a high-fat diet exercise group (HE, n = 10). NE and HE mice were exercised on a motor-driven rodent treadmill 5 days a week for 6 weeks. The mice initially ran at 50% VO2max for 20 minutes/day during the first week, and then the running intensity and time were increased to 75% VO2max (12 m/minute) for 60 minutes/day thereafter. Levels of skeletal-muscle AMPKα, ACC, and CPT1 mRNA and AMPKα and CPT1 protein expressions were analyzed. In addition, fasting serum levels of insulin, triglyceride, and cholesterol were measured. Pancreatic histology was also evaluated.

Summary of Research Findings
  • 6 weeks of exercise increased AMPKα mRNA expression by 11% in the NE and 25% in the HE group compared with their respective control groups (P <= .05 for both).
  • AMPK α protein expression increased by 37.9% in the NE group and 20.1% in the HE group compared with their sedentary controls (P < .01 for both).
  • ACC mRNA and protein expression declined in both exercise groups compared with the sedentary groups (P < .01 for both).
  • CPT1 mRNA and protein expressions were elevated in both exercise groups compared with sedentary control groups (P <= .05 for both).
  • In the NE group, pancreatic beta-cell histology was normal, and in the HE group, pancreatic beta-cell histology was improved, relative to the HC group.

Interpretation of findings/Key practice applications:

This study demonstrated that skeletal muscle AMPKα-ACC-CPT1 signaling activity is impaired by high-fat-diet-induced insulin resistance in C57BL/6 mice. Six weeks of treadmill training significantly improved skeletal-muscle AMPKα and CPT1expression and inhibited ACC expression in both normal-chow control and insulin-resistant mice. The results further demonstrated that 6 weeks of aerobic exercise can effectively ameliorate insulin resistance by increasing the expression of AMPKα, thereby activating the key enzymes that facilitate lipid metabolism. This study was limited because the rate of whole-body fat oxidation and in vitro muscle lipid uptake or oxidation could not be directly measured. Nevertheless, the authors stated that this was the first study to examine the effect of aerobic exercise on skeletal-muscle AMPKα, ACC, and CPT1 expression in normal control and insulin-resistant mice. The results further indicated that maintaining AMPK α signaling activity by regular exercise is important in preventing and treating insulin resistance caused by a high-fat diet. The findings of this study may also help explain the mechanisms by which endurance-trained athletes have high levels of cellular glucose uptake and fat metabolism.
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