Short-term Resistance Training Increases APPL1 Content in the Liver and the Insulin Sensitivity of Mice Fed a Long-term High-fat DietAcknowledgements: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES). The authors thank to Obesity and Comorbidities Research Center – OCRC, to FAPESP (2016/18488–8), University of Campinas (UNICAMP) and CNPq (process number 442542/2014–3) to all support during the experiment.
received 05 September 2018
revised 27 March 2019
accepted 28 March 2019
16 April 2019 (online)
Background APPL1, an adapter protein, interact directly with adiponectin receptors mediating adiponectin signaling and acting as a critical regulator of the crosstalk between adiponectin and insulin signaling pathway. The inadequate level of physical activity, high-calorie intake, or both lead to adverse consequences on health, like insulin resistance. On the order hand, physical exercise acts positively in the insulin action.
Purpose Here, we investigated the effects of short-term resistance training (RT) on APPL1 content and adiponectin pathway in the liver of mice fed a long-term high-fat diet.
Methods Swiss mice were distributed into 3 groups: Mice that fed a chow diet (CTR); Mice fed a high-fat diet for 16 months (HFD); and mice fed a high-fat diet for 16 months and submitted to a climbing ladder exercise (RT) for 7 days (HFD-EXE).
Results The results show that short-term RT increases the APPL1 content but wasn’t able to alter AdipoR1 and AdipoR2 content in the liver of HFD-EXE mice. However, this increase in the APPL1 content in response to RT was accompanied by improvement in the insulin sensitivity.
Conclusion In summary, our data suggested that short-term RT improves glycemic homeostasis and increases APPL1 in the hepatic tissue of mice treated with long-term high-fat diet.
- 1 Hill JO, Wyatt HR, Peters JC. Energy balance and obesity. Circulation 2012; 126: 126-132
- 2 Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121: 2111-2117
- 3 Boucher J, Kleinridders A, Kahn RC. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6 pii a009191 DOI: 10.1101/cshperspect.a009191.
- 4 Ruan H, Dong LQ. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 2016; 8: 101-109
- 5 Wang C, Xin X, Xiang R. et al. Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. J Biol Chem 2009; 284: 31608-31615
- 6 Mao X, Kikani CK, Riojas RA. et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 2006; 8: 516-523
- 7 Cheng KKY, Lam KSL, Wang Y. et al. Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 2007; 56: 1387-1394
- 8 Ryu J, Galan AK, Xin X. et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 2014; 7: 1227-1238
- 9 Mitsuuchi Y, Johnson SW, Sonoda G. et al. Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 1999; 18: 4891-4898
- 10 Cheng KKY, Iglesias MA, Lam KSL. et al. APPL1 Potentiates Insulin-Mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice. Cell Metab 2009; 9: 417-427
- 11 Schenck A, Goto-Silva L, Collinet C. et al. The Endosomal Protein Appl1 Mediates Akt Substrate Specificity and Cell Survival in Vertebrate Development. Cell 2008; 133: 486-497
- 12 Farias J, Maggi R, Tromm C. et al. Exercise training performed simultaneously to a high-fat diet reduces the degree of insulin resistance and improves adipoR1-2/APPL1 protein levels in mice. Lipids Health Dis 2012; 11: 134
- 13 Saito T, Okada S, Shimoda Y. et al. APPL1 promotes glucose uptake in response to mechanical stretch via the PKCζ-non-muscle myosin IIa pathway in C2C12 myotubes. Cell Signal 2016; 28: 1694-1702
- 14 Saito T, Jones CC, Huang S. et al. The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem 2007; 282: 32280-32287
- 15 Bird SR, Hawley JA. Update on the effects of physical activity on insulin sensitivity in humans. BMJ Open Sport Exerc Med 2017; 2: e000143
- 16 Röhling M, Herder C, Stemper T. et al. Influence of Acute and Chronic Exercise on Glucose Uptake. J Diabetes Res 2016; 2016: 1-33
- 17 Marinho R, Ropelle ER, Cintra DE. et al. Endurance exercise training increases APPL1 expression and improves insulin signaling in the hepatic tissue of diet-induced obese mice, independently of weight loss. J Cell Physiol 2012; 227: 2917-2926
- 18 Gaspar RC, Muñoz VR, Formigari GP. et al. Acute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice. Cytokine 2018; 110: 87-93
- 19 Kido K, Ato S, Yokokawa T. et al. Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats. Am J Physiol Endocrinol Metab 2018; 314: E564-E571
- 20 Muñoz VR, Gaspar RCRS, Crisol BM. et al. Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice. J Physiol Sci 2017; 1-9
- 21 Lee S, Barton ER, Sweeney HL. et al. Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats. J Appl Physiol 2004; 96: 1097-1104
- 22 Hornberger Jr. TA, Farrar RP. Physiological Hypertrophy of the FHL Muscle Following 8 Weeks of Progressive Resistance Exercise in the Rat. Can J Appl Physiol 2004; 29: 16-31
- 23 Speretta GF, Silva AA, Vendramini RC. et al. Resistance training prevents the cardiovascular changes caused by high-fat diet. Life Sci 2016; 146: 154-162
- 24 Rodrigues BDA, Pauli LSS, DE Souza CT. et al. Acute Exercise Decreases Tribbles Homolog 3 Protein Levels in the Hypothalamus of Obese Rats. Med Sci Sports Exerc 2015; 47: 1613-1623
- 25 Kumashiro N, Beddow SA, Vatner DF. et al. Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 2013; 62: 2183-2194
- 26 Kowalski GM, Kraakman MJ, Mason SA. et al. Resolution of glucose intolerance in long-term high-fat, high-sucrose-fed mice. J Endocrinol 2017; 233: 269-279
- 27 de Souza Teixeira AA, Souza CO, Biondo LA. et al. Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice. Inflammopharmacology 2018; 1-13
- 28 Toita R, Kawano T, Fujita S. et al. Increased hepatic inflammation in a normal-weight mouse after long-term high-fat diet feeding. J Toxicol Pathol 2017; 31: 43-47
- 29 Anderson NJ, King MR, Delbruck L. et al. Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice. Dis Model Mech 2014; 7: 625-633
- 30 Pauli JR, Ropelle ER, Cintra DE. et al. Acute exercise reverses aged-induced impairments in insulin signaling in rodent skeletal muscle. Mech Ageing Dev 2010; 131: 323-329
- 31 de Moura LP, Souza Pauli LS, Cintra DE. et al. Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats. Immun Ageing 2013; 10: 8 doi:10.1186/1742-4933-10-8
- 32 Eves ND, Plotnikoff RC. Resistance training and type 2 diabetes: Considerations for implementation at the population level. Diabetes Care 2006; 29: 1933-1941
- 33 Codella R, Ialacqua M, Terruzzi I. et al. May the force be with you: why resistance training is essential for subjects with type 2 diabetes mellitus without complications. Endocrine 2018; 62: 14-25
- 34 Wu Z, Jiao P, Huang X. et al. MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. J Clin Invest 2010; 120: 3901-3911
- 35 Barnard RJ, Lawani LO, Martin DA et al. Effects of maturation and aging on the skeletal muscle glucose transport system. Am J Physiol 1992