Aim. To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ). Methods. Animals were classified into control (CON), diabetes (DC), diabetic chronic exercise (DCE), and diabetic acute exercise (DAE) groups. Results. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPKα1/2, AMPKα1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPKα1/2, AMPKα2, AMPKα1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC. Conclusion. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver. 1. Introduction Leptin deficiency or dysfunction is one of the main causes for insulin resistance (IR) and lipid metabolism disorders [1, 2]. However, patients with type 2 diabetes rarely have a leptin deficiency. It has been found that the majority of type 2 diabetes patients have higher levels of body fat, but normal or increased leptin in the plasma [3–6], indicating leptin resistance (LR). Certain levels of leptin effectively could stimulate AMP-activated protein kinase (AMPK) to phosphorylate acetyl-coA carboxylase (ACC), which in turn reduces the ACC activity, decreases fatty acid synthesis [7], and increases the oxidation of fatty acid (FA) [8], consequently, maintaining the balance of lipid metabolism in the body. Studies have shown that even one week of a high fat diet can cause leptin to increase rapidly, leading to fat accumulation in peripheral tissue IR [9]. Obese persons with high serum leptin levels tend to experience a downregulation of leptin receptor in hypothalamus, adipose tissue, and liver [10], which causes peripheral tissues to become LR and promotes lipid accumulation [11–13]. Excessive lipid deposition in nonfat tissue has been known to have a toxic effect on cells and to reduce sensitivity to insulin, eventually leading to
References
[1]
K. F. Petersen, E. A. Oral, S. Dufour et al., “Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy,” Journal of Clinical Investigation, vol. 109, no. 10, pp. 1345–1350, 2002.
[2]
E. A. Oral, V. Simha, E. Ruiz et al., “Leptin-replacement therapy for lipodystrophy,” The New England Journal of Medicine, vol. 346, no. 8, pp. 570–578, 2002.
[3]
J. M. Friedman, “Modern science versus the stigma of obesity,” Nature Medicine, vol. 10, no. 6, pp. 563–569, 2004.
[4]
M. Mapfei, J. Halaas, E. Ravussin et al., “Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects,” Nature Medicine, vol. 1, no. 11, pp. 1155–1161, 1995.
[5]
A. Widjaja, I. M. Stratton, R. Horn, R. R. Holman, R. Turner, and G. Brabant, “UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 2, pp. 654–657, 1997.
[6]
S. B. Heymsfield, A. S. Greenberg, K. Fujioka et al., “Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial,” Journal of the American Medical Association, vol. 282, no. 16, pp. 1568–1575, 1999.
[7]
A. Sriwijitkamol, D. K. Coletta, E. Wajcberg et al., “Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study,” Diabetes, vol. 56, no. 3, pp. 836–848, 2007.
[8]
A. E. Jeukendrup, “Regulation of fat metabolism in skeletal muscle,” Annals of the New York Academy of Sciences, vol. 967, pp. 217–235, 2002.
[9]
K. L. Mullen, J. Pritchard, I. Ritchie et al., “Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 296, no. 2, pp. R243–R251, 2009.
[10]
X. J. Yi, H. Wang, and Q. P. Li, “Exercise on the sexual development and the fat leptin receptor mRNA expression in the high-fat die female rats,” Zhongguo Ying Yong Sheng Li Xue Za Zhi, vol. 25, no. 4, pp. 454–542, 2009.
[11]
T. Fuentes, I. Ara, A. Guadalupe-Grau et al., “Leptin receptor 170 kDa (OB-R170) protein expression is reduced in obese human skeletal muscle: a potential mechanism of leptin resistance,” Experimental Physiology, vol. 95, no. 1, pp. 160–171, 2010.
[12]
G. R. Steinberg, D. J. Dyck, J. Calles-Escandon et al., “Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle,” Journal of Biological Chemistry, vol. 277, no. 11, pp. 8854–8860, 2002.
[13]
G. K. Bandyopadhyay, J. G. Yu, J. Ofrecio, and J. M. Olefsky, “Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects,” Diabetes, vol. 55, no. 8, pp. 2277–2285, 2006.
[14]
B. Vozarova, N. Stefan, R. S. Lindsay et al., “High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes,” Diabetes, vol. 51, no. 6, pp. 1889–1895, 2002.
[15]
D. J. Chiang, M. T. Pritchard, and L. E. Nagy, “Obesity, diabetes mellitus, and liver fibrosis,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 300, no. 5, pp. G697–G702, 2011.
[16]
M. Lazo and J. M. Clark, “The epidemiology of nonalcoholic fatty liver disease: a global perspective,” Seminars in Liver Disease, vol. 28, no. 4, pp. 339–350, 2008.
[17]
R. Lautam？ki, R. Borra, P. Iozzo et al., “Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes,” American Journal of Physiology—Endocrinology and Metabolism, vol. 291, no. 2, pp. E282–E290, 2006.
[18]
K. A. Krawczewski Carhuatanta, G. Demuro, M. H. Tsch？p, P. T. Pfluger, S. C. Benoit, and S. Obici, “Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity,” Endocrinology, vol. 152, no. 7, pp. 2655–2664, 2011.
[19]
R. Sari, M. K. Balci, N. Balci, and U. Karayalcin, “Acute effect of exercise on plasma leptin level and insulin resistance in obese women with stable caloric intake,” Endocrine Research, vol. 32, no. 1-2, pp. 9–17, 2007.
[20]
J. Zhao, Y. Tian, J. Xu, D. Liu, X. Wang, and B. Zhao, “Endurance exercise is a leptin signaling mimetic in hypothalamus of Wistar rats,” Lipids in Health and Disease, vol. 10, article 225, 2011.
[21]
C. M. Patterson, S. G. Bouret, A. A. Dunn-Meynell, and B. E. Levin, “Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 296, no. 3, pp. R537–R548, 2009.
[22]
N. B. Ruderman, H. Park, V. K. Kaushik et al., “AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise,” Acta Physiologica Scandinavica, vol. 178, no. 4, pp. 435–442, 2003.
[23]
S. Cao, B. Li, X. Yi et al., “Effects of exercise on AMPK signaling and downstream components to PI3K in rat with type 2 diabetes,” PLoS ONE, vol. 7, no. 12, Article ID e51709, 2012.
[24]
K. Srinivasan, B. Viswanad, L. Asrat, C. L. Kaul, and P. Ramarao, “Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening,” Pharmacological Research, vol. 52, no. 4, pp. 313–320, 2005.
[25]
M. Zhang, X.-Y. Lv, J. Li, Z.-G. Xu, and L. Chen, “The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model,” Experimental Diabetes Research, vol. 2008, Article ID 704045, 9 pages, 2008.
[26]
E. Luciano, E. M. Carneiro, C. R. Carvalho et al., “Endurance training improves responsiveness to insulin and modulates insulin signal transduction through the phosphatidylinositol 3-kinase/Akt-1 pathway,” European Journal of Endocrinology, vol. 147, no. 1, pp. 149–157, 2002.
[27]
A. V. Chibalin, M. Yu, J. W. Ryder et al., “Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 1, pp. 38–43, 2000.
[28]
U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage T4,” Nature, vol. 227, no. 5259, pp. 680–685, 1970.
[29]
S. Tanaka, T. Hayashi, T. Toyoda et al., “High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle,” Metabolism, vol. 56, no. 12, pp. 1719–1728, 2007.
[30]
K. F. Petersen and G. I. Shulman, “Etiology of insulin resistance,” American Journal of Medicine, vol. 119, no. 5, pp. S10–S16, 2006.
[31]
P.-J. Hsiao, K.-K. Kuo, S.-J. Shin et al., “Significant correlations between severe fatty liver and risk factors for metabolic syndrome,” Journal of Gastroenterology and Hepatology, vol. 22, no. 12, pp. 2118–2123, 2007.
[32]
G. Targher and G. Arcaro, “Non-alcoholic fatty liver disease and increased risk of cardiovascular disease,” Atherosclerosis, vol. 191, no. 2, pp. 235–240, 2007.
[33]
E. Fabbrini, S. Sullivan, and S. Klein, “Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications,” Hepatology, vol. 51, no. 2, pp. 679–689, 2010.
[34]
E. K. Speliotes, J. M. Massaro, U. Hoffmann et al., “Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham heart study,” Hepatology, vol. 51, no. 6, pp. 1979–1987, 2010.
[35]
E. Fabbrini, F. Magkos, B. S. Mohammed et al., “Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 36, pp. 15430–15435, 2009.
[36]
M. Shimabukuro, K. Koyama, G. Chen et al., “Direct antidiabetic effect of leptin through triglyceride depletion of tissues,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4637–4641, 1997.
[37]
R. H. Unger, “The Physiology of Cellular Liporegulation,” Annual Review of Physiology, vol. 65, pp. 333–347, 2003.
[38]
M. Palou, T. Priego, J. Sánchez et al., “Sequential changes in the expression of genes involved in lipid metabolism in adipose tissue and liver in response to fasting,” Pflugers Archiv European Journal of Physiology, vol. 456, no. 5, pp. 825–836, 2008.
[39]
Y. Minokoshi, T. Alquier, H. Furukawa et al., “AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus,” Nature, vol. 428, no. 6982, pp. 569–574, 2004.
[40]
L. Miyamoto, K. Ebihara, T. Kusakabe et al., “Leptin activates hepatic 5′-AMP-activated protein kinase through sympathetic nervous system and ?1-adrenergic receptor:a potential mechanism for improvement of fatty liver in lipodystrophy by leptin,” The Journal of Biological Chemistry, vol. 287, no. 48, pp. 40441–40447, 2012.
[41]
X. Yu, S. McCorkle, M. Wang et al., “Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition,” Diabetologia, vol. 47, no. 11, pp. 2012–2021, 2004.
[42]
K. A. Krawczewski Carhuatanta, G. Demuro, M. H. Tsch？p, P. T. Pfluger, S. C. Benoit, and S. Obici, “Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity,” Endocrinology, vol. 152, no. 7, pp. 2655–2664, 2011.
[43]
M.-S. Gauthier, K. Couturier, A. Charbonneau, and J.-M. Lavoie, “Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile,” International Journal of Obesity, vol. 28, no. 8, pp. 1064–1071, 2004.
[44]
G. R. Steinberg, A. C. Smith, S. Wormald, P. Malenfant, C. Collier, and D. J. Dyck, “Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle,” American Journal of Physiology—Endocrinology and Metabolism, vol. 286, no. 1, pp. E57–E63, 2004.
[45]
L. Roselli-Rehfuss, K. G. Mountjoy, L. S. Robbins et al., “Identification of a receptor for γ melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 19, pp. 8856–8860, 1993.
[46]
G. R. Steinberg, A. C. Smith, S. Wormald, P. Malenfant, C. Collier, and D. J. Dyck, “Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle,” American Journal of Physiology—Endocrinology and Metabolism, vol. 286, no. 1, pp. E57–E63, 2004.
[47]
S. Yasari, D. Wang, D. Prud'homme, M. Jankowski, J. Gutkowska, and J.-M. Lavoie, “Exercise training decreases plasma leptin levels and the expression of hepatic leptin receptor-a, -b, and, -e in rats,” Molecular and Cellular Biochemistry, vol. 324, no. 1-2, pp. 13–20, 2009.
[48]
J. Zhao, Y. Tian, J. Xu, D. Liu, X. Wang, and B. Zhao, “Endurance exercise is a leptin signaling mimetic in hypothalamus of Wistar rats,” Lipids in Health and Disease, vol. 10, article 225, 2011.
[49]
H. Olmedillas, J. Sanchis-Moysi, T. Fuentes et al., “Muscle hypertrophy and increased expression of leptin receptors in the musculus triceps brachii of the dominant arm in professional tennis players,” European Journal of Applied Physiology, vol. 108, no. 4, pp. 749–758, 2010.
[50]
I. R. W. Ritchie, R. A. Gulli, L. E. Stefanyk, E. Harasim, A. Chabowski, and D. J. Dyck, “Restoration of skeletal muscle leptin response does not precede the exercise-induced recovery of insulin-stimulated glucose uptake in high-fat-fed rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 300, no. 2, pp. R492–R500, 2011.
[51]
K. Takekoshi, M. Fukuhara, Z. Quin et al., “Long-term exercise stimulates adenosine monophosphate-activated protein kinase activity and subunit expression in rat visceral adipose tissue and liver,” Metabolism, vol. 55, no. 8, pp. 1122–1128, 2006.
[52]
J. P. Little, A. Safdar, N. Cermak, M. A. Tarnopolsky, and M. J. Gibala, “Acute endurance exercise increases the nuclear abundance of PGC-1α in trained human skeletal muscle,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 298, no. 4, pp. R912–R917, 2010.
[53]
R. S. Lee-Young, G. Koufogiannis, B. J. Canny, and G. K. McConell, “Acute exercise does not cause sustained elevations in AMPK signaling or expression,” Medicine and Science in Sports and Exercise, vol. 40, no. 8, pp. 1490–1494, 2008.
[54]
H.-J. Koh, M. F. Hirshman, H. He et al., “Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes,” Biochemical Journal, vol. 403, no. 3, pp. 473–481, 2007.
