Activated Translation Signaling in Placenta from Pregnant Women with Gestational Diabetes Mellitus: Possible Role of Leptin

Abstract

Placentas from gestational diabetes (GDM) suffer from structural and functional changes including overgrowth. That is why we aimed to study [³H]-leucine incorporation into protein in addition to translation signaling in placenta from GDM. Thus, we investigated the expression of leptin and leptin receptor (LEPR), as well as the activation state of signaling proteins regulating protein synthesis, such as mTOR, S6 Kinase, EIF4E-BP1, EIF4E, and eEF2 by measuring protein phosphorylation by immunoblot. [³H]-Leucine incorporation into protein also was determined in trophoblastic placenta explants from GDM and control pregnancy. We found that leptin and LEPR expression are increased in placentas from GDM and the translation machinery activity as well as [³H]-leucine incorporation into protein were higher in placentas from GDM compared with placentas from control pregnancy. In conclusion, protein synthesis rate is increased in placenta from GDM patients, and this may be due, at least in part, by the activation of translation signaling. The increased expression of leptin and LEPR may contribute to these effects. These results may provide a possible mechanism for the previously observed increase in placenta growth in GDM.

Key words

leptin - LEPR - trophoblastic cells - mTOR - EIF4EBP1 - translation - gestational diabetes

• References

• 1 Gabbe SG. Gestational diabetes mellitus. N Engl J Med 1986; 315: 1025-1026
• 2 Barnes-Powell LL. Infants of diabetic mothers: the effects of hyperglycemia on the fetus and neonate. Neonatal Netw 2007; 26: 283-290
• 3 Jahan S, Ahmed CM, Zinnat R, Hasan Z, Habib SH, Saha S, Ali L. Influence of maternal diabetes on serum leptinemic and insulinemic status of the offspring: a case study of selected patients in a tertiary care hospital in Bangladesh. Diabetes Metab Syndr 2011; 5: 33-37
• 4 Hagbard L, Svanborg A. Prognosis of diabetes mellitus with onset during pregnancy. A clinical study of seventy-one cases. Diabetes 1960; 9: 296-302
• 5 Kjos SL, Peters RK, Xiang A, Henry OA, Montoro M, Buchanan TA. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995; 44: 586-591
• 6 O’Sullivan JB. Body weight and subsequent diabetes mellitus. JAMA 1982; 248: 949-952
• 7 Guibourdenche J, Porquet D, Evain-Brion D. Placental hormones and fetal growth. Gynecol Obstet Fertil 2001; 29: 532-533
• 8 Perez-Perez A, Maymo J, Duenas JL, Goberna R, Calvo JC, Varone C, Sanchez-Margalet V. Leptin prevents apoptosis of trophoblastic cells by activation of MAPK pathway. Arch Biochem Biophys 2008; 477: 390-395
• 9 Perez-Perez A, Gambino Y, Maymo J, Goberna R, Fabiani F, Varone C, Sanchez-Margalet V. MAPK and PI3K activities are required for leptin stimulation of protein synthesis in human trophoblastic cells. Biochem Biophys Res Commun 2010; 396: 956-960
• 10 Gambino YP, Maymo JL, Perez-Perez A, Duenas JL, Sanchez-Margalet V, Calvo JC, Varone CL. 17Beta-Estradiol Enhances Leptin Expression in Human Placental Cells Through Genomic and Nongenomic Actions. Biol Reprod 2010; 83: 42-51
• 11 Maymo JL, Perez PA, Sanchez-Margalet V, Duenas JL, Calvo JC, Varone CL. Upregulation of placental leptin by human chorionic gonadotropin. Endocrinology 2009; 150: 304-313
• 12 Maymo JL, Perez PA, Duenas JL, Calvo JC, Sanchez-Margalet V, Varone CL. Regulation of placental leptin expression by cyclic adenosine 5′-monophosphate involves cross talk between protein kinase A and mitogen-activated protein kinase signaling pathways. Endocrinology 2010; 151: 3738-3751
• 13 Magarinos MP, Sanchez-Margalet V, Kotler M, Calvo JC, Varone CL. Leptin promotes cell proliferation and survival of trophoblastic cells. Biol Reprod 2007; 76: 203-210
• 14 Ericsson A, Saljo K, Sjostrand E, Jansson N, Prasad PD, Powell TL, Jansson T. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol 2007; 581: 1323-1332
• 15 Taricco E, Radaelli T, Nobile de Santis MS, Cetin I. Foetal and placental weights in relation to maternal characteristics in gestational diabetes. Placenta 2003; 24: 343-347
• 16 Briana DD, Malamitsi-Puchner A. Reviews: adipocytokines in normal and complicated pregnancies. Reprod Sci 2009; 16: 921-937
• 17 Proud CG, Denton RM. Molecular mechanisms for the control of translation by insulin. Biochem J 1997; 328: 329-341
• 18 Perez-Perez A, Maymo J, Gambino Y, Duenas JL, Goberna R, Varone C, Sanchez-Margalet V. Leptin stimulates protein synthesis-activating translation machinery in human trophoblastic cells. Biol Reprod 2009; 81: 826-832
• 19 Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N, Lawrence Jr JC. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 1994; 266: 653-656
• 20 Kleijn M, Scheper GC, Voorma HO, Thomas AA. Regulation of translation initiation factors by signal transduction. Eur J Biochem 1998; 253: 531-544
• 21 Minich WB, Balasta ML, Goss DJ, Rhoads RE. Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF-4E: increased cap affinity of the phosphorylated form. Proc Natl Acad Sci USA 1994; 91: 7668-7672
• 22 Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 1994; 370: 71-75
• 23 Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science 1998; 279: 707-710
• 24 Carlberg U, Nilsson A, Nygard O. Functional properties of phosphorylated elongation factor 2. Eur J Biochem 1990; 191: 639-645
• 25 Ryazanov AG, Shestakova EA, Natapov PG. Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 1988; 334: 170-173
• 26 Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3: 1101-1108
• 27 Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J, Hauguel-De MS. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes 1998; 47: 847-850
• 28 Uzelac PS, Li X, Lin J, Neese LD, Lin L, Nakajima ST, Bohler H, Lei Z. Dysregulation of leptin and testosterone production and their receptor expression in the human placenta with gestational diabetes mellitus. Placenta 2010; 31: 581-588
• 29 Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol 2001; 212: 83-91
• 30 Sanchez-Margalet V, Goldfine ID, Vlahos CJ, Sung CK. Role of phosphatidylinositol-3-kinase in insulin receptor signaling: studies with inhibitor, LY294002. Biochem Biophys Res Commun 1994; 204: 446-452
• 31 Boileau P, Cauzac M, Pereira MA, Girard J, Hauguel-De MS. Dissociation between insulin-mediated signaling pathways and biological effects in placental cells: role of protein kinase B and MAPK phosphorylation. Endocrinology 2001; 142: 3974-3979
• 32 Pullen N, Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett 1997; 410: 78-82
• 33 Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab 2003; 88: 1205-1211
• 34 Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997; 3: 1029-1033
• 35 Bajoria R, Sooranna SR, Ward BS, Chatterjee R. Prospective function of placental leptin at maternal-fetal interface. Placenta 2002; 23: 103-115
• 36 Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 2002; 277: 34601-34609
• 37 Meissner U, Ostreicher I, Allabauer I, Rascher W, Dotsch J. Synergistic effects of hypoxia and insulin are regulated by different transcriptional elements of the human leptin promoter. Biochem Biophys Res Commun 2003; 303: 707-712
• 38 Najib S, Sanchez-Margalet V. Human leptin promotes survival of human circulating blood monocytes prone to apoptosis by activation of p42/44 MAPK pathway. Cell Immunol 2002; 220: 143-149
• 39 Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol 1999; 194: 6-11
• 40 Meissner U, Spranger R, Lehner M, Allabauer I, Rascher W, Dotsch J. Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis. Eur J Endocrinol 2005; 153: 455-461
• 41 Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell Immunol 2001; 211: 30-36
• 42 Desoye G, Hauguel-De MS. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care 2007; 30 (Suppl. 02) S120-S126
• 43 Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS, Burton GJ. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 2008; 173: 451-462