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  • Original Article
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Relation between human LPIN1, hypoxia and endoplasmic reticulum stress genes in subcutaneous and visceral adipose tissue

International Journal of Obesity volume 34, pages 679–686 (2010)Cite this article

Subjects

Abstract

Context:

LPIN1 is the phosphatidic acid phosphatase that produces 1,2-diacylglycerol, and thus it is related to the synthesis of triglycerides in the adipocyte. LPIN1 has a role in lipid synthesis and nuclear receptor coactivation, both of which may be involved in lipid homeostasis and metabolism. Among others, hypoxia and endoplasmic reticulum (ER) stress are being shown to be related to the adipose dysfunction found in human obesity.

Objective:

The aim of this study was to analyze LPIN1 gene expression in human adipose tissue in parallel with several hypoxia, angiogenic, ER stress and peroxisome proliferator-activated receptor (PPAR)-related genes in human obesity.

Design and Patients:

Gene expression was quantified in abdominal (subcutaneous and visceral) adipose tissue from 62 subjects.

Results:

We have shown a marked association between LPIN1 and PPARα gene expression both in subcutaneous and visceral adipose tissues. Similarly, a strong interdependence with vascular endothelial growth factor (VEGF) gene expression was also described; in fact, LPIN1 and VEGF expression levels were significantly decreased with obesity to a similar extent.

Conclusion:

These associations might suggest a possible role of LPIN1 in stress conditions that occur in chronic obesity and underlie insulin resistance.

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Abbreviations

ACTB:

β-actin

BMI:

body mass index

CHOP10:

C/EBP-homologous protein 10

CRP:

C reactive protein

DBP:

diastolic blood pressure

ER:

endoplasmic reticulum

GLUT1:

glucose transporter 1

HIF-1α:

hypoxia-inducible factor 1α

HSP90:

heat shock protein HSP 90-alpha

LPIN1 :

lipin 1 gene

PGC-1α:

PPARγ coactivator 1α

PPAR:

peroxisome proliferator-activated receptor

PPIA:

cyclophilin 1A

SAT:

subcutaneous adipose tissue

sIL-6:

soluble interleukin 6

VAT:

visceral adipose tissue

VEGF:

vascular endothelial growth factor

XBP1:

X-box binding protein-1

References

  1. Storlien L, Oakes ND, Kelley DE . Metabolic flexibility. Proc Nutr Soc 2004; 63: 363–368.

    Article  CAS  Google Scholar 

  2. Savage DB, Petersen KF, Shulman GI . Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 2007; 87: 507–520.

    Article  CAS  Google Scholar 

  3. Shoelson SE, Lee J, Goldfine AB . Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793–1801.

    Article  CAS  Google Scholar 

  4. Goossens GH . The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008; 94: 206–218.

    Article  CAS  Google Scholar 

  5. Sundar Rajan S, Srinivasan V, Balasubramanyam M, Tatu U . Endoplasmic reticulum (ER) stress & diabetes. Indian J Med Res 2007; 125: 411–424.

    CAS  PubMed  Google Scholar 

  6. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005; 54: 2277–2286.

    Article  CAS  Google Scholar 

  7. Poulain-Godefroy O, Lecoeur C, Pattou F, Frühbeck G, Froguel P . Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 2008; 295: R1–R7.

    Article  CAS  Google Scholar 

  8. Trayhurn P, Wang B, Wood IS . HIF-1alpha protein rather than mRNA as a marker of hypoxia in adipose tissue in obesity: focus on ‘inflammation is associated with a decrease of lipogenic factors in omental fat in women,’ by Poulain-Godefroy et al. Am J Physiol Regul Integr Comp Physiol 2008; 295: R1097.

    Article  CAS  Google Scholar 

  9. Wang B, Wood IS, Trayhurn P . Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 2007; 455: 479–492.

    Article  CAS  Google Scholar 

  10. Wang B, Wood IS, Trayhurn P . Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes. J Endocrinol 2008; 198: 127–134.

    Article  CAS  Google Scholar 

  11. Trayhurn P, Wang B, Wood IS . Hypoxia and the endocrine and signalling role of white adipose tissue. Arch Physiol Biochem 2008; 114: 267–276.

    Article  CAS  Google Scholar 

  12. Ron D, Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–529.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Reue K, Dwyer JR . Lipin proteins and metabolic homeostasis. J Lipid Res 2009; 50: S109–S114.

    Article  Google Scholar 

  15. Miranda M, Chacón MR, Gómez J, Megía A, Ceperuelo-Mallafré V, Veloso S et al. Human subcutaneous adipose tissue LPIN1 expression in obesity, type 2 diabetes mellitus, and human immunodeficiency virus—associated lipodystrophy syndrome. Metabolism 2007; 56: 1518–1526.

    Article  CAS  Google Scholar 

  16. van Harmelen V, Rydén M, Sjölin E, Hoffstedt J . A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. J Lipid Res 2007; 48: 201–206.

    Article  CAS  Google Scholar 

  17. Suviolahti E, Reue K, Cantor RM, Phan J, Gentile M, Naukkarinen J et al. Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism. Hum Mol Genet 2006; 15: 377–386.

    Article  CAS  Google Scholar 

  18. Yao-Borengasser A, Rasouli N, Varma V, Miles LM, Phanavanh B, Starks TN et al. Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation. Diabetes 2006; 55: 2811–2818.

    Article  CAS  Google Scholar 

  19. Donkor J, Sparks LM, Xie H, Smith SR, Reue K . Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men. J Clin Endocrinol Metab 2008; 93: 233–239.

    Article  CAS  Google Scholar 

  20. Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE et al. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006; 4: 199–210.

    Article  CAS  Google Scholar 

  21. Han GS, Wu WI, Carman GM . The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 2006; 281: 9210–9218.

    Article  CAS  Google Scholar 

  22. Gowri PM, Sengupta S, Bertera S, Katzenellenbogen BS . Lipin1 regulation by estrogen in uterus and liver: implications for diabetes and fertility. Endocrinology 2007; 148: 3685–3693.

    Article  CAS  Google Scholar 

  23. Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Krishna V et al. Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res 2003; 93: e88–e97.

    Article  CAS  Google Scholar 

  24. World Health Organization. Obesity: Preventing and Managing the Global Epidemic. In: WHO (eds). WHO Technical Report Series 894. World Health Organization: Geneva, Switzerland, 2000. pp 9.

  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment; insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  26. Grimsey N, Han GS, O'Hara L, Rochford JJ, Carman GM, Siniossoglou S . Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2. J Biol Chem 2008; 283: 29166–29174.

    Article  CAS  Google Scholar 

  27. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.

    Article  CAS  Google Scholar 

  28. Li P, Zhu Z, Lu Y, Granneman JG . Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor-alpha. Am J Physiol Endocrinol Metab 2005; 289: E617–E626.

    Article  CAS  Google Scholar 

  29. Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D et al. Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 2003; 278: 33370–33376.

    Article  CAS  Google Scholar 

  30. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S et al. Hypoxia-inducible factor 1 alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29: 4467–4483.

    Article  CAS  Google Scholar 

  31. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901–911.

    Article  CAS  Google Scholar 

  32. Diraison F, Dusserre E, Vidal H, Sothier M, Beylot M . Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2002; 282: E46–E51.

    Article  CAS  Google Scholar 

  33. Rausch ME, Weisberg S, Vardhana P, Tortoriello DV . Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes 2008; 32: 451–463.

    Article  CAS  Google Scholar 

  34. Ye J, Gao Z, Yin J, He Q . 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 2007; 293: E1118–E1128.

    Article  CAS  Google Scholar 

  35. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 2009; 58: 718–725.

    Article  CAS  Google Scholar 

  36. Silha JV, Krsek M, Sucharda P, Murphy LJ . Angiogenic factors are elevated in overweight and obese individuals. Int J Obes 2005; 29: 1308–1314.

    Article  CAS  Google Scholar 

  37. Gómez-Ambrosi J, Catalán V, Rodríguez A, Ramírez B, Silva C, Gil MJ et al. Involvement of serum vascular endothelial growth factor family members in the development of obesity in mice and humans. J Nutr Biochem 2009. e-pub ahead of print 15 July 2009; doi: 10.1016/j.jnutbio.2009.05.004.

    Article  Google Scholar 

  38. Widberg CH, Newell FS, Bachmann AW, Ramnoruth SN, Spelta MC, Whitehead JP et al. Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes. Am J Physiol Endocrinol Metab 2009; 296: E121–E131.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by FIS 07/1024 and FIS 08/1195 from the Spanish Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo with the participation of the European Regional Development Fund (ERDF). XE is supported by a fellowship from the JdlC programme and Grant JDCI20071020. We gratefully acknowledge the invaluable collaboration of Symeon Siniossoglou (Cambridge Institute for Medical Research (CIMR), Cambridge, UK), the Servei de Recursos Científics i Tècnics of Universitat Rovira i Virgili, the statistical assistance of Pilar Hernández from the IISPV, and the technical assistance of Verònica Alba from the URV. CIBER de Diabetes y Enfermedades Metabólicas Asociadas is an ISCIII project. This work was supported by FIS 07/1024 and FIS 08/1195 from the Spanish Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo.

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Authors and Affiliations

  1. Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, IISPV, Tarragona, Spain

    M Miranda, X Escoté, V Ceperuelo-Mallafré, A Megía, S Näf & J Vendrell

  2. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain

    M Miranda, X Escoté, V Ceperuelo-Mallafré, A Megía & J Vendrell

  3. Surgery Department, ‘St. Pau i Sta. Tecla’ Hospital, Tarragona, Spain

    E Caubet

  4. Endocrinology and Diabetes Unit, University Hospital of Bellvitge, L'Hospitalet de Llobregat, Spain

    J M Gómez

  5. Diabetes Service, Endocrinology and Nutrition, Hospital of Sabadell, Parc Taulí Institute, Sabadell, Spain

    J M González-Clemente

  6. Surgery Department, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain

    V Vicente

  7. Universitat Rovira i Virgili, Tarragona, Spain

    V Ceperuelo-Mallafré & J Vendrell

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  1. M Miranda
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Correspondence to M Miranda.

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Miranda, M., Escoté, X., Ceperuelo-Mallafré, V. et al. Relation between human LPIN1, hypoxia and endoplasmic reticulum stress genes in subcutaneous and visceral adipose tissue. Int J Obes 34, 679–686 (2010). https://doi.org/10.1038/ijo.2009.290

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