Regulation of hepatic TRB3/Akt interaction induced by physical exercise and its effect on the hepatic glucose production in an insulin resistance state

Diabetology & Metabolic Syndrome

Leandro Pereira de Moura²  José Rodrigo Pauli²  Ricardo José Gomes³  Vitor Rosetto Muñoz²  Rania A. Mekary¹  Rodolfo Marinho² 

[1] Department of Nutrition, Harvard T. Chan School of Public Health, Boston, MA, USA;Faculty of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccaria, 1300, Jardim Santa Luzia, Limeira, SP, Brazil;Department of Biosciences, São Paulo Federal University (UNIFESP), Santos, SP, Brazil

关键词: Hepatic glucose production;    Liver;    Insulin resistance;    TRB3;    Physical exercise;   

Others  :  1225026
DOI  :  10.1186/s13098-015-0064-x

 received in 2015-04-29, accepted in 2015-08-10,  发布年份 2015

【 摘 要 】

To maintain euglycemia in healthy organisms, hepatic glucose production is increased during fasting and decreased during the postprandial period. This whole process is supported by insulin levels. These responses are associated with the insulin signaling pathway and the reduction in the activity of key gluconeogenic enzymes, resulting in a decrease of hepatic glucose production. On the other hand, defects in the liver insulin signaling pathway might promote inadequate suppression of gluconeogenesis, leading to hyperglycemia during fasting and after meals. The hepatocyte nuclear factor 4, the transcription cofactor PGC1-α, and the transcription factor Foxo1 have fundamental roles in regulating gluconeogenesis. The loss of insulin action is associated with the production of pro-inflammatory biomolecules in obesity conditions. Among the molecular mechanisms involved, we emphasize in this review the participation of TRB3 protein (a mammalian homolog of Drosophila tribbles), which is able to inhibit Akt activity and, thereby, maintain Foxo1 activity in the nucleus of hepatocytes, inducing hyperglycemia. In contrast, physical exercise has been shown as an important tool to reduce insulin resistance in the liver by reducing the inflammatory process, including the inhibition of TRB3 and, therefore, suppressing gluconeogenesis. The understanding of these new mechanisms by which physical exercise regulates glucose homeostasis has critical importance for the understanding and prevention of diabetes.

【 授权许可】

   
2015 Marinho et al.

【 图 表 】

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【 参考文献 】

• [1]American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43–8.
• [2]Matthaei S, Stumvoll M, Kellerer M, Haring HU: Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev 2000, 21:585-618.
• [3]Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM: A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92:829-839.
• [4]Ozcan L, Cristina de Souza J, Harari AA, Backs J, Olson EN, Tabas I: Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab 2013, 18:803-815.
• [5]Ozcan L, Wong CCL, Li G, Xu T, Pajvani U, Park SKR, Wronska A, Chen B-X, Marks AR, Fukamizu A, Backs J, Singer HA, Yates JR, Accili D, Tabas I: Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab 2012, 15:739-751.
• [6]Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H, Iwashita S, Kako K, Kishi T, Kasuya Y, Fukamizu A: Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 2007, 19:519-527.
• [7]De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJA, Velloso LA: Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005, 146:4192-4199.
• [8]Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J, Yates J 3rd, Montminy M: Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 2007, 449:366-369.
• [9]Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney G, Zhu W, Vanhoutte PM, Kraegen EW, Xu A: APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metab 2009, 9:417-427.
• [10]Cintra DE, Pauli JR, Araujo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, Velloso LA: Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol 2008, 48:628-637.
• [11]Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393-403.
• [12]Ropelle ER, Pauli JR, Prada PO, de Souza CT, Picardi PK, Faria MC, Cintra DE, Fernandes MF, Flores MB, Velloso LA, Saad MJ, Carvalheira JB: Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol 2006, 577(Pt 3):997-1007.
• [13]Da Silva ASR, Pauli JR, Ropelle ER, Oliveira AG, Cintra DE, De Souza CT, Velloso LA, Carvalheira JBC, Saad MJA: Exercise intensity, inflammatory signaling, and insulin resistance in obese rats. Med Sci Sports Exerc 2010, 42:2180-2188.
• [14]Hawley JA, Lessard SJ: Exercise training-induced improvements in insulin action. Acta Physiol 2008, 192:127-135.
• [15]Pauli JR, Ropelle ER, Cintra DE, Carvalho-Filho MA, Moraes JC, De Souza CT, Velloso LA, Carvalheira JBC, Saad MJA: Acute physical exercise reverses S-nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet-induced obese Wistar rats. J Physiol 2008, 586:659-671.
• [16]Oliveira AG, Carvalho BM, Tobar N, Ropelle ER, Pauli JR, Bagarolli RA, Guadagnini D, Carvalheira JB, Saad MJ: Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes 2011, 60:784-796.
• [17]Pauli JR, Cintra DE, De Souza CT, Ropelle ER: Novos mecanismos pelos quais o exercício físico melhora a resistência à insulina no músculo esquelético. Arq Bras Endocrinol Metabol 2009, 53(4):399-408.
• [18]Da Luz G, Frederico MJ, da Silva S, Vitto MF, Cesconetto PA, de Pinho RA, Pauli JR, Silva AS, Cintra DE, Ropelle ER, De Souza CT: Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. Eur J Appl Physiol 2011, 111:2015-2023.
• [19]Masson GS, Nair AR, Dange RB, Silva-Soares PP, Michelini LC, Francis J: Toll-like receptor 4 promotes autonomic dysfunction, inflammation and microglia activation in the hypothalamic paraventricular nucleus: role of endoplasmic reticulum stress. PLoS One 2015, 10:e0122850.
• [20]Cnop M, Foufelle F, Velloso LA: Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012, 18:59-68.
• [21]Yao L, Kan EM, Lu J, Hao A, Dheen ST, Kaur C, Ling E-A: Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. J Neuroinflammation 2013, 10:23. BioMed Central Full Text
• [22]Pierre N, Deldicque L, Barbé C, Naslain D, Cani PD, Francaux M: Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS One 2013, 8:e65061.
• [23]Koh H-J, Toyoda T, Didesch MM, Lee M-Y, Sleeman MW, Kulkarni RN, Musi N, Hirshman MF, Goodyear LJ: Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Nat Commun 1871, 2013:4.
• [24]Wang S, Kaufman RJ: The impact of the unfolded protein response on human disease. J Cell Biol 2012, 197:857-867.
• [25]Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS: Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 2011, 473:528-531.
• [26]Hansen LH, Gromada J, Bouchelouche P, Whitmore T, Jelinek L, Kindsvogel W, Nishimura E: Glucagon-mediated Ca2+ signaling in BHK cells expressing cloned human glucagon receptors. Am J Physiol Cell Physiol 1998, 274:C1552-C1562.
• [27]Wang Y, Li G, Goode J, Paz JC, Ouyang K, Screaton R, Fischer WH, Chen J, Tabas I, Montminy M: Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 2012, 485:128-132.
• [28]Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science (80). 2003;300:1574–7.
• [29]Lima AF, Ropelle ER, Pauli JR, Cintra DE, Frederico MJ, Pinho RA, Velloso LA, De Souza CT: Acute exercise reduces insulin resistance-induced TRB3 expression and amelioration of the hepatic production of glucose in the liver of diabetic mice. J Cell Physiol 2009, 221:92-97.
• [30]Sung HY, Guan H, Czibula A, King AR, Eder K, Heath E, Suvarna SK, Dower SK, Wilson AG, Francis SE, Crossman DC, Kiss-Toth E: Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways. J Biol Chem 2007, 282:18379-18387.
• [31]Tang M, Zhong M, Shang Y, Lin H, Deng J, Jiang H, Lu H, Zhang Y, Zhang W: Differential regulation of collagen types I and III expression in cardiac fibroblasts by AGEs through TRB3/MAPK signaling pathway. Cell Mol Life Sci 2008, 65:2924-2932.
• [32]Naiki T, Saijou E, Miyaoka Y, Sekine K, Miyajima A: TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta. J Biol Chem 2007, 282:24075-24082.
• [33]Iynedjian PB: Lack of evidence for a role of TRB3/NIPK as an inhibitor of PKB-mediated insulin signalling in primary hepatocytes. Biochem J 2005, 386(Pt 1):113-118.
• [34]Matsumoto M, Han S, Kitamura T, Accili D: Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 2006, 116:2464-2472.
• [35]Koo S-H, Satoh H, Herzig S, Lee C-H, Hedrick S, Kulkarni R, Evans RM, Olefsky J, Montminy M: PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 2004, 10:530-534.
• [36]Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 2005, 24:1243-1255.
• [37]Koh H-J, Arnolds DE, Fujii N, Tran TT, Rogers MJ, Jessen N, Li Y, Liew CW, Ho RC, Hirshman MF, Kulkarni RN, Kahn CR, Goodyear LJ: Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Mol Cell Biol 2006, 26:8217-8227.
• [38]Matsushima R, Harada N, Webster NJ, Tsutsumi YM, Nakaya Y: Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity. J Biol Chem 2006, 281:29719-29729.
• [39]Yu J, Xiao F, Guo Y, Deng J, Liu B, Zhang Q, Li K, Wang C, Chen S, Guo F: Hepatic phosphoserine aminotransferase 1 regulates insulin sensitivity in mice via tribbles homolog 3. Diabetes 2015, 64:1591-1602.
• [40]Prudente S, Hribal ML, Flex E, Turchi F, Morini E, De Cosmo S, Bacci S, Tassi V, Cardellini M, Lauro R, Sesti G, Dallapiccola B, Trischitta V: The functional Q84R polymorphism of mammalian tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in caucasians from Italy. Diabetes 2005, 54:2807-2811.
• [41]Matos A, Ropelle ER, Pauli JR, Frederico MJ, de Pinho RA, Velloso LA, De Souza CT: Acute exercise reverses TRB3 expression in the skeletal muscle and ameliorates whole body insulin sensitivity in diabetic mice. Acta Physiol 2010, 198:61-69.
• [42]Ropelle ER, Pauli JR, Cintra DE, Frederico MJ, de Pinho RA, Velloso LA, De Souza CT: Acute exercise modulates the Foxo1/PGC-1alpha pathway in the liver of diet-induced obesity rats. J Physiol 2009, 587(Pt 9):2069-2076.
• [43]De Souza CT, Frederico MJ, da Luz G, Cintra DE, Ropelle ER, Pauli JR, Velloso LA: Acute exercise reduces hepatic glucose production through inhibition of the Foxo1/HNF-4alpha pathway in insulin resistant mice. J Physiol 2010, 588(Pt 12):2239-2253.
• [44]Marinho R, Ropelle ER, Cintra DE, De Souza CT, Da Silva ASR, Bertoli FC, Colantonio E, D’Almeida V, Pauli JR: 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.
• [45]Hoene M, Lehmann R, Hennige AM, Pohl AK, Haring HU, Schleicher ED, Weigert C: Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise. J Physiol 2009, 587(Pt 1):241-252.
• [46]Schenck A, Goto-Silva L, Collinet C, Rhinn M, Giner A, Habermann B, Brand M, Zerial M: The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 2008, 133:486-497.