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Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes

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Abstract

Hypoxia modulates white adipose tissue function, and this includes stimulating glucose uptake and the expression of facilitative glucose transporters (particularly GLUT1) in adipocytes. This study has examined the effect of hypoxia on lactate release from adipocytes and whether the monocarboxylate transporters that mediate lactate transport (MCTs1–4) are expressed in human adipocytes and are induced by low O2 tension. Exposure of human Simpson-Golabi-Behmel syndrome adipocytes to 1% O2 for 24 h resulted in increased lactate release (2.3-fold) compared with cells in normoxia (21% O2). Screening by reverse transcription polymerase chain reaction indicated that the genes encoding MCT1, MCT2, and MCT4 are expressed in human adipose tissue, and in adipocytes and preadipocytes in culture. Hypoxia (48 h) increased MCT1 (8.5-fold) and MCT4 (14.3-fold) messenger RNA (mRNA) levels in human adipocytes, but decreased MCT2 mRNA (fourfold). MCT1 protein level was also increased (2.7-fold at 48 h) by hypoxia, but there was no change in MCT4 protein. The changes in MCT gene expression induced by hypoxia were reversed on return to normoxia. Treatment with the hypoxia mimetic CoCl2 resulted in up-regulation of MCT1 (up to twofold) and MCT4 (fivefold) mRNA level, but there was no significant effect on MCT2 expression. It is concluded that hypoxia increases lactate release from adipocytes and modulates MCT expression in a type-specific manner, with MCT1 and MCT4 expression being hypoxia-inducible transcription factor-1 (HIF-1) dependent. Increased lactate production and monocarboxylate transporter expression are likely to be key components of the adaptive response of adipocytes to low O2 tension as adipose tissue mass expands in obesity.

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References

  1. Brahimi-Horn MC, Pouysségur J (2007) Oxygen, a source of life and stress. FEBS Lett 581:3582–3591

    Article  CAS  PubMed  Google Scholar 

  2. Chen B, Lam KSL, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RLC, Zhang J, Xu A (2006) Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 341:549–556

    Article  CAS  PubMed  Google Scholar 

  3. Choi CS, Kim YB, Lee FN, Zabolotny JM, Kahn BB, Youn JH (2002) Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling. Am J Physiol Endocrinol Metab 283:E233–E240

    CAS  PubMed  Google Scholar 

  4. DiGirolamo M, Newby FD, Lovejoy J (1992) Lactate production in adipose tissue: a regulated function with extra-adipose implications. FASEB J 6:2405–2412

    CAS  PubMed  Google Scholar 

  5. Froberg MK, Gerhart DZ, Enerson BE, Manivel C, Guzman-Paz M, Seacotte N, Drewes LR (2001) Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. NeuroReport 12:761–765

    Article  CAS  PubMed  Google Scholar 

  6. Green H, Halestrap A, Mockett C, O'Toole D, Grant S, Ouyang J (2002) Increases in muscle MCT are associated with reductions in muscle lactate after a single exercise session in humans. Am J Physiol Endocrinol Metab 282:E154–E160

    CAS  PubMed  Google Scholar 

  7. Gregor MF, Hotamisligil GS (2007) Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905–1914

    Article  CAS  PubMed  Google Scholar 

  8. Hajduch E, Heyes RR, Watt PW, Hundal HS (2000) Lactate transport in rat adipocytes: identification of monocarboxylate transporter 1 (MCT1) and its modulation during streptozotocin-induced diabetes. FEBS Lett 479:89–92

    Article  CAS  PubMed  Google Scholar 

  9. Halestrap A, Meredith D (2004) The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflügers Archiv Eur J Physiol 447:619–628

    Article  CAS  Google Scholar 

  10. Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA (2007) Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J 21:2602–2612

    Article  CAS  PubMed  Google Scholar 

  11. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–911

    Article  CAS  PubMed  Google Scholar 

  12. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  CAS  PubMed  Google Scholar 

  13. Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ, Mirzadegan T, Mazur C, Kamme F, Lovenberg TW (2009) Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 284:2811–2822

    Article  CAS  PubMed  Google Scholar 

  14. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(ΔΔC(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  15. Lolmède K, de Saint D, Front V, Galitzky J, Lafontan M, Bouloumié A (2003) Effects of hypoxia on the expression of proangiogenic factors in differentiated 3 T3-F442A adipocytes. Int J Obesity 27:1187–1195

    Article  Google Scholar 

  16. Lovejoy J, Newby FD, Gebhart SS, DiGirolamo M (1992) Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin. Metabolism 41:22–27

    Article  CAS  PubMed  Google Scholar 

  17. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K (1996) cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221:286–289

    Article  CAS  PubMed  Google Scholar 

  18. McClelland GB, Brooks GA (2002) Changes in MCT 1, MCT 4, and LDH expression are tissue specific in rats after long-term hypobaric hypoxia. J Appl Physiol 92:1573–1584

    CAS  PubMed  Google Scholar 

  19. Meredith D, Christian HC (2008) The SLC16 monocaboxylate transporter family. Xenobiotica 38:1072–1106

    Article  CAS  PubMed  Google Scholar 

  20. Newby FD, Bayo F, Thacker SV, Sykes M, DiGirolamo M (1989) Effects of streptozocin-induced diabetes on glucose metabolism and lactate release by isolated fat cells from young lean and older, moderately obese rats. Diabetes 38:237–243

    Article  CAS  PubMed  Google Scholar 

  21. Ohlson LO, Larsson B, Björntorp P, Eriksson H, Svardsudd K, Welin L, Tibblin G, Wilhelmsen L (1988) Risk factors for type 2 (non-insulin-dependent) diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913. Diabetologia 31:798–805

    Article  CAS  PubMed  Google Scholar 

  22. Ord JJ, Streeter EH, Roberts IS, Cranston D, Harris AL (2005) Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer. Br J Cancer 93:346–354

    Article  CAS  PubMed  Google Scholar 

  23. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR (2009) Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58:718–725

    Article  CAS  PubMed  Google Scholar 

  24. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14

    Article  CAS  PubMed  Google Scholar 

  25. Py G, Eydoux N, Lambert K, Chapot R, Koulmann N, Sanchez H, Bahi L, Peinnequin A, Mercier J, Bigard AX (2005) Role of hypoxia-induced anorexia and right ventricular hypertrophy on lactate transport and MCT expression in rat muscle. Metabolism 54:634–644

    Article  CAS  PubMed  Google Scholar 

  26. Qvisth V, Hagström-Toft E, Moberg E, Sjoberg S, Bolinder J (2007) Lactate release from adipose tissue and skeletal muscle in vivo: defective insulin regulation in insulin-resistant obese women. Am J Physiol Endocrinol Metab 292:E709–E714

    Article  CAS  PubMed  Google Scholar 

  27. Rajala MW, Scherer PE (2003) The adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773

    Article  CAS  PubMed  Google Scholar 

  28. Rausch ME, Weisberg SP, Vardhana P, Tortorielllo DV (2008) Obesity in C57BL/6 J mice is characterised by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obesity 32:451–463

    Article  CAS  Google Scholar 

  29. Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti J-F, Giorgetti-Peraldi S (2009) Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58:95–103

    Article  CAS  PubMed  Google Scholar 

  30. Rocha S (2007) Gene regulation under low oxygen: holding your breath for transcription. Trends Biochem Sci 32:389–397

    Article  CAS  PubMed  Google Scholar 

  31. Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853

    Article  CAS  PubMed  Google Scholar 

  32. Samuvel DJ, Sundararaj KP, Nareika A, Lopes-Virella MF, Huang Y (2009) Lactate Boosts TLR4 signaling and NF-ΚB pathway-mediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. J Immunol 182:2476–2484

    Article  CAS  PubMed  Google Scholar 

  33. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749

    Article  CAS  PubMed  Google Scholar 

  34. Semenza GL (2001) HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13:167–171

    Article  CAS  PubMed  Google Scholar 

  35. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  36. Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339

    Article  CAS  PubMed  Google Scholar 

  37. Trayhurn P, Wang B, Wood IS (2008) Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 100:227–235

    Article  CAS  PubMed  Google Scholar 

  38. Trayhurn P, Wood IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355

    Article  CAS  PubMed  Google Scholar 

  39. Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J Biol Chem 281:9030–9037

    Article  CAS  PubMed  Google Scholar 

  40. van der Meer DL, van den Thillart GE, Witte F, de Bakker MA, Besser J, Richardson MK, Spaink HP, Leito JT, Bagowski CP (2005) Gene expression profiling of the long-term adaptive response to hypoxia in the gills of adult zebrafish. Am J Physiol Regul Integr Comp Physiol 289:R1512–R1519

    PubMed  Google Scholar 

  41. Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H (2001) Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obesity 25:8–15

    Article  CAS  Google Scholar 

  42. Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflügers Archiv Eur J Physiol 455:479–492

    Article  CAS  Google Scholar 

  43. Wang B, Wood IS, Trayhurn P (2008) PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochem Biophys Res Commun 368:88–93

    Article  CAS  PubMed  Google Scholar 

  44. Wood IS, Wang B, Lorente-Cebrián S, Trayhurn P (2007) Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes. Biochem Biophys Res Commun 361:468–473

    Article  PubMed  Google Scholar 

  45. Ye J, Gao Z, Yin J, He Q (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118–E1128

    Article  CAS  PubMed  Google Scholar 

  46. Zawadzki JK, Wolfe RR, Mott DM, Lillioja S, Howard BV, Bogardus C (1988) Increased rate of Cori cycle in obese subjects with NIDDM and effect of weight reduction. Diabetes 37:154–159

    Article  CAS  PubMed  Google Scholar 

  47. Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homolog. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Professor Martin Wabisch (University of Ulm, Germany) for the provision of SGBS cells, Professor Soraya Shirazi-Beechey (University of Liverpool) for the antibody to MCT1, and to Professor Andrew Halestrap (University of Bristol, UK) for the antibody to MCT4. We acknowledge the financial support of the Biotechnology and Biological Sciences Research Council (UK) and the award of a Fellowship to FPH from the Foundation Alfonso Martín Escudero (Madrid, Spain). PT is a member of COST BM0602.

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  1. Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, Duncan Building, Liverpool, L69 3GA, UK

    Fátima Pérez de Heredia, I. Stuart Wood & Paul Trayhurn

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  1. Fátima Pérez de Heredia
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Correspondence to Paul Trayhurn.

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Pérez de Heredia, F., Wood, I.S. & Trayhurn, P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch - Eur J Physiol 459, 509–518 (2010). https://doi.org/10.1007/s00424-009-0750-3

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