Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism

  • Loes P. M. Duivenvoorde
  • Evert M. van Schothorst
  • Davina Derous
  • Inge van der Stelt
  • Jinit Masania
  • Naila Rabbani
  • Paul J. Thornalley
  • Jaap KeijerEmail author
Integrative physiology


Challenge tests stress homeostasis and may reveal deviations in health that remain masked under unchallenged conditions. Ideally, challenge tests are non-invasive and applicable in an early phase of an animal experiment. Oxygen restriction (OxR; based on ambient, mild normobaric hypoxia) is a non-invasive challenge test that measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome. To test whether OxR can be used to reveal early diet-induced health effects, we exposed mice to a low-fat (LF) or high-fat (HF) diet for only 5 days. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and epididymal white adipose tissue (eWAT) and serum markers for e.g. protein glycation and oxidation. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR; however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. Cumulatively, OxR is a promising new method to test food products on potential beneficial effects for human health.


Hypoxia Metabolism High-fat diet Obesity Oxidative stress Indirect calorimetry 



This work was supported by the European Union’s Seventh Framework Program FP7 2007–2013 under grant agreement no. 244995 (BIOCLAIMS Project). Furthermore, we would like to thank all members of Human and Animal Physiology for their helpful contributions, especially Hans Swarts, Dylan Eikelenboom and Esther Steenbergh for their help during the animal experiment and the analysis of gene expression.

Ethical standards

The experimental protocol was approved by the Animal Welfare Committee of Wageningen University, Wageningen, The Netherlands (DEC2012035).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

424_2014_1553_MOESM1_ESM.pdf (45 kb)
Suppl. fig. 1 Schematic overview of the study design and exposure to OxR. The complete study lasted for three weeks. 48 male mice arrived at 10 weeks of age. After three weeks on the low-fat diet, mice were stratified and individually housed in the indirect calorimetry system. Mice could adapt to the InCa system for 24 h after which 24 mice received a fresh batch of LF diet and 24 mice switched to the high-fat diet. After 5 days of HF- or LF feeding, mice were exposed to OxR or remained under normal air conditions for 6 hours. Mice were fasted by providing them a restricted amount of feed at the start of the dark phase (18.00 h) preceding the OxR or normoxic challenge. The restricted amount of feed is generally consumed within 6 hours (around 0.00 h). Around 5.00 h, all mice were in a fasted state (RER < 0.8). For the LFo and HFo mice, oxygen is decreased from 20.9 % to 12 % from 7.00 h to 7.30 h. LFn and HFn mice remained under normoxic conditions. Indirect calorimetry values during OxR or normoxia were then recorded from 7.30 h to 13.30 h, after which mice were immediately sacrificed. (PDF 44 kb)
424_2014_1553_MOESM2_ESM.pdf (51 kb)
Suppl. fig. 2 Relative gene expression in liver tissue and WAT of LF and HF mice that were either exposed to OxR or normoxic air. Gene expression in liver (a) and WAT (b) was calculated relatively to the geometric mean of the reference genes. Sod1, superoxide dismutase 1; Sod2, superoxide dismutase 2; Ucp2, uncoupling protein 2; Slc2a2, solute carrier family 2 (facilitated glucose transporter; Glut2); Pdk1, pyruvate dehydrogenase kinase 1; Pklr, pyruvate kinase; Pck1phosphoenolpyruvatecarboxykinase 1 (Pepck); Ldha, lactate dehydrogenase A; Slc16a1, solute carrier family 16 (Mct1); Pcx, pyruvate carboxylase; Me1, malic enzyme; Txnrd2, thioredoxinreductase 2; Vegfa, vascular endothelial growth factor A; Ppargrc1a peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1a); Cs, citrate synthase; Cpt1a, carnitinepalmitoyltransferase 1a; Pnpla2, patatin-like phospholipase domain containing 2; Acaca, acetyl-Coenzyme A carboxylase alpha; Acly, ATP citrate lyase; Elovl6, ELOVL family member 6, elongation of long chain fatty acids; Fasn, fatty acid synthase; Scd1, stearoyl-Coenzyme A desaturase 1 (PDF 50 kb)
424_2014_1553_MOESM3_ESM.docx (17 kb)
Suppl. Table 1 (DOCX 17 kb)
424_2014_1553_MOESM4_ESM.docx (14 kb)
Suppl. Table 2 (DOCX 14 kb)


  1. 1.
    Aon MA, Stanley BA, Sivakumaran V, Kembro JM, O’Rourke B, Paolocci N, Cortassa S (2012) Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: an experimental-computational study. J Gen Physiol 139:479–491. doi: 10.1085/jgp.201210772 CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Asterholm IW, Scherer PE (2010) Enhanced metabolic flexibility associated with elevated adiponectin levels. Am J Pathol 176:1364–1376. doi: 10.2353/ajpath.2010.090647 CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Bartelt A, Heeren J (2012) The holy grail of metabolic disease: brown adipose tissue. Curr Opin Lipidol 23:190–195. doi: 10.1097/MOL.0b013e328352dcef CrossRefPubMedGoogle Scholar
  4. 4.
    Baze MM, Schlauch K, Hayes JP (2010) Gene expression of the liver in response to chronic hypoxia. Physiol Genomics. doi: 10.1152/physiolgenomics.00075.2009 PubMedCentralPubMedGoogle Scholar
  5. 5.
    Butler AA, Kozak LP (2010) A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 59:323–329. doi: 10.2337/db09-1471 CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Cannon B, Nedergaard J (2011) Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214:242–253. doi: 10.1242/jeb.050989 CrossRefPubMedGoogle Scholar
  7. 7.
    Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS (2008) Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134:933–944. doi: 10.1016/j.cell.2008.07.048 CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Carstens MT, Goedecke JH, Dugas L, Evans J, Kroff J, Levitt NS, Lambert EV (2013) Fasting substrate oxidation in relation to habitual dietary fat intake and insulin resistance in non-diabetic women: a case for metabolic flexibility? Nutr Metab (Lond) 10:8. doi: 10.1186/1743-7075-10-8 CrossRefGoogle Scholar
  9. 9.
    Charlot K, Pichon A, Richalet JP, Chapelot D (2013) Effects of a high-carbohydrate versus high-protein meal on acute responses to hypoxia at rest and exercise. Eur J Appl Physiol 113:691–702. doi: 10.1007/s00421-012-2472-z CrossRefPubMedGoogle Scholar
  10. 10.
    Choi JH, Park MJ, Kim KW, Choi YH, Park SH, An WG, Yang US, Cheong J (2005) Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis by transcriptional regulation. FEBS Lett 579:2795–2801. doi: 10.1016/j.febslet.2005.03.097 CrossRefPubMedGoogle Scholar
  11. 11.
    David JM, Chatziioannou AF, Taschereau R, Wang H, Stout DB (2013) The hidden cost of housing practices: using noninvasive imaging to quantify the metabolic demands of chronic cold stress of laboratory mice. Comp Med 63:386–391PubMedCentralPubMedGoogle Scholar
  12. 12.
    Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY (2011) Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 19:2167–2174. doi: 10.1038/oby.2011.240 CrossRefGoogle Scholar
  13. 13.
    Duivenvoorde LP, van Schothorst EM, Bunschoten A, Keijer J (2011) Dietary restriction of mice on a high-fat diet induces substrate efficiency and improves metabolic health. J Mol Endocrinol 47:81–97. doi: 10.1530/JME-11-0001 CrossRefGoogle Scholar
  14. 14.
    Duivenvoorde LPM, van Schothorst EM, Swarts HJ, Keijer J (2014) Assessment of metabolic flexibility of old and adult mice using three non-invasive, indirect calorimetry-based treatments. J Gerontol A Biol Sci Med Sci. doi: 10.1093/gerona/glu027 PubMedGoogle Scholar
  15. 15.
    Eccleston HB, Andringa KK, Betancourt AM, King AL, Mantena SK, Swain TM, Tinsley HN, Nolte RN, Nagy TR, Abrams GA, Bailey SM (2011) Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. Antioxid Redox Signal 15:447–459. doi: 10.1089/ars.2010.3395 CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Eissing L, Scherer T, Todter K, Knippschild U, Greve JW, Buurman WA, Pinnschmidt HO, Rensen SS, Wolf AM, Bartelt A, Heeren J, Buettner C, Scheja L (2013) De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat Commun 4:1528. doi: 10.1038/ncomms2537 CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9:203–209. doi: 10.1016/j.cmet.2008.12.014 CrossRefPubMedGoogle Scholar
  18. 18.
    Gamboa JL, Andrade FH (2010) Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia. Am J Physiol Regul Integr Comp Physiol 298:R575–R583. doi: 10.1152/ajpregu.00320.2009 CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Golja P, Flander P, Klemenc M, Maver J, Princi T (2008) Carbohydrate ingestion improves oxygen delivery in acute hypoxia. High Alt Med Biol 9:53–62. doi: 10.1089/ham.2008.1021 CrossRefPubMedGoogle Scholar
  20. 20.
    Hoevenaars FP, Keijer J, Swarts HJ, Snaas-Alders S, Bekkenkamp-Grovenstein M, van Schothorst EM (2013) Effects of dietary history on energy metabolism and physiological parameters in C57BL/6J mice. Exp Physiol 98:1053–1062. doi: 10.1113/expphysiol.2012.069518 CrossRefPubMedGoogle Scholar
  21. 21.
    Hoevenaars FP, van Schothorst EM, Horakova O, Voigt A, Rossmeisl M, Pico C, Caimari A, Kopecky J, Klaus S, Keijer J (2012) BIOCLAIMS standard diet (BIOsd): a reference diet for nutritional physiology. Genes Nutr 7:399–404. doi: 10.1007/s12263-011-0262-6 CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Horakova O, Medrikova D, van Schothorst EM, Bunschoten A, Flachs P, Kus V, Kuda O, Bardova K, Janovska P, Hensler M, Rossmeisl M, Wang-Sattler R, Prehn C, Adamski J, Illig T, Keijer J, Kopecky J (2012) Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice. PLoS One 7:e43764. doi: 10.1371/journal.pone.0043764 CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Hutter JF, Schweickhardt C, Piper HM, Spieckermann PG (1984) Inhibition of fatty acid oxidation and decrease of oxygen consumption of working rat heart by 4-bromocrotonic acid. J Mol Cell Cardiol 16:105–108CrossRefPubMedGoogle Scholar
  24. 24.
    Jequier E, Acheson K, Schutz Y (1987) Assessment of energy expenditure and fuel utilization in man. Annu Rev Nutr 7:187–208. doi: 10.1146/ CrossRefPubMedGoogle Scholar
  25. 25.
    Kelly KR, Williamson DL, Fealy CE, Kriz DA, Krishnan RK, Huang H, Ahn J, Loomis JL, Kirwan JP (2010) Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans. Metabolism 59:200–205. doi: 10.1016/j.metabol.2009.07.014 CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Kim DH, Gutierrez-Aguilar R, Kim HJ, Woods SC, Seeley RJ (2013) Increased adipose tissue hypoxia and capacity for angiogenesis and inflammation in young diet-sensitive C57 mice compared with diet-resistant FVB mice. Int J Obes (Lond) 37:853–860. doi: 10.1038/ijo.2012.141 CrossRefGoogle Scholar
  27. 27.
    Larsen JJ, Hansen JM, Olsen NV, Galbo H, Dela F (1997) The effect of altitude hypoxia on glucose homeostasis in men. J Physiol 504(Pt 1):241–249CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Li J, Grigoryev DN, Ye SQ, Thorne L, Schwartz AR, Smith PL, O’Donnell CP (1985) Polotsky VY (2005) Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 99:1643–1648. doi: 10.1152/japplphysiol.00522.2005 CrossRefGoogle Scholar
  29. 29.
    Livesey G, Elia M (1988) Estimation of energy expenditure, net carbohydrate utilization, and net fat oxidation and synthesis by indirect calorimetry: evaluation of errors with special reference to the detailed composition of fuels. Am J Clin Nutr 47:608–628PubMedGoogle Scholar
  30. 30.
    Louis M, Punjabi NM (2009) Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol 106:1538–1544. doi: 10.1152/japplphysiol.91523.2008 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Masschelein E, Van Thienen R, D’Hulst G, Hespel P, Thomis M, Deldicque L (2014) Acute environmental hypoxia induces LC3 lipidation in a genotype-dependent manner. FASEB J 28:1022–1034. doi: 10.1096/fj.13-239863 CrossRefPubMedGoogle Scholar
  32. 32.
    Mazzatti D, Lim FL, O’Hara A, Wood IS, Trayhurn P (2012) A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes. Arch Physiol Biochem 118:112–120. doi: 10.3109/13813455.2012.654611 CrossRefPubMedGoogle Scholar
  33. 33.
    Mimura Y, Furuya K (1995) Mechanisms of adaptation to hypoxia in energy metabolism in rats. J Am Coll Surg 181:437–443PubMedGoogle Scholar
  34. 34.
    Montgomery MK, Hallahan NL, Brown SH, Liu M, Mitchell TW, Cooney GJ, Turner N (2013) Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56:1129–1139. doi: 10.1007/s00125-013-2846-8 CrossRefPubMedGoogle Scholar
  35. 35.
    Mortola JP, Rezzonico R, Lanthier C (1989) Ventilation and oxygen consumption during acute hypoxia in newborn mammals: a comparative analysis. Respir Physiol 78:31–43CrossRefPubMedGoogle Scholar
  36. 36.
    Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG (2000) Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study JAMA 283:1829–1836Google Scholar
  37. 37.
    Oltmanns KM, Gehring H, Rudolf S, Schultes B, Rook S, Schweiger U, Born J, Fehm HL, Peters A (2004) Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 169:1231–1237. doi: 10.1164/rccm.200308-1200OC CrossRefPubMedGoogle Scholar
  38. 38.
    Ostreicher I, Meissner U, Plank C, Allabauer I, Castrop H, Rascher W, Dotsch J (2009) Altered leptin secretion in hyperinsulinemic mice under hypoxic conditions. Regul Pept 153:25–29. doi: 10.1016/j.regpep.2008.11.011 CrossRefPubMedGoogle Scholar
  39. 39.
    Peronnet F, Massicotte D (1991) Table of nonprotein respiratory quotient: an update. Can J Sport Sci 16:23–29PubMedGoogle Scholar
  40. 40.
    Pison CM, Chauvin C, Perrault H, Schwebel C, Lafond JL, Boujet C, Leverve XM (1998) In vivo hypoxic exposure impairs metabolic adaptations to a 48 hour fast in rats. Eur Respir J 12:658–665CrossRefPubMedGoogle Scholar
  41. 41.
    Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118:829–838. doi: 10.1172/JCI34275 CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Rabbani N, Chittari MV, Bodmer CW, Zehnder D, Ceriello A, Thornalley PJ (2010) Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin. Diabetes 59:1038–1045. doi: 10.2337/db09-1455 CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Rabbani N, Shaheen F, Anwar A, Masania J, Thornalley PJ (2014) Assay of methylglyoxal-derived protein and nucleotide AGEs. Biochemical Society Transactions in pressGoogle Scholar
  44. 44.
    Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S (2009) Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58:95–103. doi: 10.2337/db08-0457 CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Reinke C, Bevans-Fonti S, Drager LF, Shin MK, Polotsky VY (2011) Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes. J Appl Physiol 111:881–890. doi: 10.1152/japplphysiol.00492.2011 CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ (2002) Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A 99:10730–10735. doi: 10.1073/pnas.162349799 CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Saito K, Ohta Y, Sami M, Kanda T, Kato H (2010) Effect of mild restriction of food intake on gene expression profile in the liver of young rats: reference data for in vivo nutrigenomics study. Br J Nutr 104:941–950. doi: 10.1017/S0007114510001625 CrossRefPubMedGoogle Scholar
  48. 48.
    Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763PubMedGoogle Scholar
  49. 49.
    Takeuchi M, Kimura S, Kuroda J, Ashihara E, Kawatani M, Osada H, Umezawa K, Yasui E, Imoto M, Tsuruo T, Yokota A, Tanaka R, Nagao R, Nakahata T, Fujiyama Y, Maekawa T (2010) Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment. Cell Death Differ 17:1211–1220. doi: 10.1038/cdd.2010.6 CrossRefPubMedGoogle Scholar
  50. 50.
    Taylor CT (2008) Mitochondria and cellular oxygen sensing in the HIF pathway. Biochem J 409:19–26. doi: 10.1042/BJ20071249 CrossRefPubMedGoogle Scholar
  51. 51.
    Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592. doi: 10.1042/BJ20030763 CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Thornalley PJ, Rabbani N (2014) Detection of oxidized and glycated proteins in clinical samples using mass spectrometry—a user’s perspective. Biochim Biophys Acta 1840:818–829. doi: 10.1016/j.bbagen.2013.03.025 CrossRefPubMedGoogle Scholar
  53. 53.
    Tschop MH, Speakman JR, Arch JR, Auwerx J, Bruning JC, Chan L, Eckel RH, Farese RV Jr, Galgani JE, Hambly C, Herman MA, Horvath TL, Kahn BB, Kozma SC, Maratos-Flier E, Muller TD, Munzberg H, Pfluger PT, Plum L, Reitman ML, Rahmouni K, Shulman GI, Thomas G, Kahn CR, Ravussin E (2012) A guide to analysis of mouse energy metabolism. Nat Methods 9:57–63. doi: 10.1038/nmeth.1806 CrossRefGoogle Scholar
  54. 54.
    Ukropcova B, McNeil M, Sereda O, de Jonge L, Xie H, Bray GA, Smith SR (2005) Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor. J Clin Invest 115:1934–1941. doi: 10.1172/JCI24332 CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    van Ommen B, Keijer J, Heil SG, Kaput J (2009) Challenging homeostasis to define biomarkers for nutrition related health. Mol Nutr Food Res 53:795–804. doi: 10.1002/mnfr.200800390 CrossRefPubMedGoogle Scholar
  56. 56.
    Van Schothorst EM, Franssen-van Hal N, Schaap MM, Pennings J, Hoebee B, Keijer J (2005) Adipose gene expression patterns of weight gain suggest counteracting steroid hormone synthesis. Obes Res 13:1031–1041. doi: 10.1038/oby.2005.121 CrossRefPubMedGoogle Scholar
  57. 57.
    Voigt A, Agnew K, van Schothorst EM, Keijer J, Klaus S (2013) Short-term, high fat feeding-induced changes in white adipose tissue gene expression are highly predictive for long-term changes. Mol Nutr Food Res 57:1423–1434. doi: 10.1002/mnfr.201200671 CrossRefPubMedGoogle Scholar
  58. 58.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112:1796–1808. doi: 10.1172/Jci2000319246 CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Xu HY, Barnes GT, Yang Q, Tan Q, Yang DS, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–1830. doi: 10.1172/Jci200319451 CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J (2009) Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 296:E333–E342. doi: 10.1152/ajpendo.90760.2008 CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Loes P. M. Duivenvoorde
    • 1
  • Evert M. van Schothorst
    • 1
  • Davina Derous
    • 1
  • Inge van der Stelt
    • 1
  • Jinit Masania
    • 2
  • Naila Rabbani
    • 2
  • Paul J. Thornalley
    • 2
  • Jaap Keijer
    • 1
    Email author
  1. 1.Human and Animal PhysiologyWageningen UniversityWageningenThe Netherlands
  2. 2.Clinical Sciences Research Laboratories, Warwick Medical SchoolUniversity of Warwick, University HospitalCoventryUK

Personalised recommendations