Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Adipose tissue lipin expression levels distinguish HIV patients with and without lipodystrophy

International Journal of Obesity volume 31, pages 449–456 (2007)Cite this article

Abstract

Objective:

Lipodystrophy is the major complication of antiretroviral therapy in HIV-infected patients. Its pathophysiology is not well understood, but has been linked to antiadipogenic effects of antiretroviral drugs. Lipin represents a newly characterized protein that is critical for adipocyte differentiation, and lipin deficiency leads to lipodystrophy in the mouse. The objective of this study was to determine whether altered lipin gene expression is associated with HIV lipodystrophy in humans.

Design:

We measured lipin mRNA levels in subcutaneous abdominal and femoral-gluteal adipose tissue biopsies from HIV-infected patients with or without lipodystrophy, and in healthy controls. Real-time reverse transcription-PCR was performed to quantitate total lipin expression levels, and expression of two lipin isoforms (lipin-α and -β) that are generated by alternative mRNA splicing.

Results:

As predicted from studies with mice, lipin mRNA levels were correlated with limb fat mass in HIV patients, with lower lipin levels in patients with lipodystrophy than those without lipodystrophy. Unexpectedly, however, this was explained by an increase in lipin-β expression in HIV patients without lipodystrophy compared to patients with lipodystrophy and control subjects. In addition, lipin expression levels were inversely correlated with adipose tissue expression of inflammatory cytokines interleukin (IL)-6, IL-8 and IL-18, which typically increase in HIV-associated lipoatrophy.

Conclusions:

Elevated lipin expression levels are associated both with the maintenance of greater fat mass and lower cytokine expression in HIV-infected patients. Based on the demonstrated role for lipin in promoting lipogenic gene expression, these observations raise the possibility that variations in lipin levels may contribute to variations in adipose tissue mass and function that distinguish HIV patients with and without lipodystrophy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG . An objective case definition of lipodystrophy in HIV-infected adults: a case–control study. Lancet 2003; 361: 726–735.

    Article  CAS  Google Scholar 

  2. Hansen AE, Lindegaard B, Obel N, Andersen O, Nielsen H, Gerstoft J . Pronounced lipoatrophy in HIV-infected men receiving HAART for more than six years compared with background population. HIV Med 2005; 7: 38–45.

    Article  Google Scholar 

  3. Bacchetti P, Gripshover B, Grunfeld C, Heymsfield S, McCreath H, Osmond D et al. Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr 2005; 40: 121–131.

    Article  Google Scholar 

  4. Garg A . Acquired and inherited lipodystrophies. N Engl J Med 2004; 350: 1220–1234.

    Article  CAS  Google Scholar 

  5. Carr A, Samaras K, Chisholm DJ, Cooper DA . Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–1883.

    Article  CAS  Google Scholar 

  6. Lawrence R . Lipodystrophy and hepatomegaly with diabetes, lipemia and other metabolic disturbances: a case throwing new light on the action of insulin. Lancet 1946; 1: 724–731.

    Article  Google Scholar 

  7. Rossini AA . Lipoatrophic diabetes. In: Marble A, Krall LP, Bradley RF, Christlieb AR, Soeldner JS (eds). Joslin's Diabetes Mellitus. Lea & Febiger: Philadelphia, 1985. pp 834–842.

    Google Scholar 

  8. Zhang B, MacNaul K, Szalkowski D, Li Z, Berger J, Moller DE . Inhibition of adipocyte differentiation by HIV protease inhibitors. J Clin Endocrinol Metab 1999; 84: 4274–4277.

    Article  CAS  Google Scholar 

  9. Dowell P, Flexner C, Kwiterovich PO, Lane MD . Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem 2000; 275: 41325–41332.

    Article  CAS  Google Scholar 

  10. Wentworth JM, Burris TP, Chatterjee VK . HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer. J Endocrinol 2000; 16: R7–R10.

    Article  Google Scholar 

  11. Lenhard JM, Furfine ES, Jain RG, Ittoop O, Orband-Miller LA, Blanchard SG et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res 2000; 4: 121–129.

    Article  Google Scholar 

  12. Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J . The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 2001; 50: 1378–1388.

    Article  CAS  Google Scholar 

  13. Caron M, Auclair M, Sterlingot H, Kornprobst M, Capeau J . Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation. Aids 2003; 17: 2437–2444.

    Article  CAS  Google Scholar 

  14. Caron M, Auclair M, Lagathu C, Lombes A, Walker UA, Kornprobst M et al. The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. Aids 2004; 18: 2127–2136.

    Article  CAS  Google Scholar 

  15. Reue K, Xu P, Wang XP, Slavin BG . Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J Lipid Res 2000; 4: 1067–1076.

    Google Scholar 

  16. Reue K, Peterfy M . Mouse models of lipodystrophy. Curr Atheroscler Rep 2000; 2: 390–396.

    Article  CAS  Google Scholar 

  17. Peterfy M, Phan J, Xu P, Reue K . Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 2001; 27: 121–124.

    Article  CAS  Google Scholar 

  18. Phan J, Reue K . Lipin, a lipodystrophy and obesity gene. Cell Metab 2005; 1: 73–83.

    Article  CAS  Google Scholar 

  19. Phan J, Peterfy M, Reue K . Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro. J Biol Chem 2004; 279: 29558–29564.

    Article  CAS  Google Scholar 

  20. 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 

  21. Huffman TA, Mothe-Satney I, Lawrence Jr JC . Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci USA 2002; 99: 1047–1052.

    Article  CAS  Google Scholar 

  22. Peterfy M, Phan J, Reue K . Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem 2005; 280: 32883–32889.

    Article  CAS  Google Scholar 

  23. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA . Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 2093–2099.

    Article  CAS  Google Scholar 

  24. Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S . Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 1999; 84: 1932–1937.

    CAS  PubMed  Google Scholar 

  25. Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, Steensberg A et al. Interleukin-6 production by contracting human skeletal muscle: autocrine regulation by IL-6. Biochem Biophys Res Commun 2003; 310: 550–554.

    Article  CAS  Google Scholar 

  26. Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002; 359: 1026–1031.

    Article  CAS  Google Scholar 

  27. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC . Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 2000; 25: 312–321.

    Article  CAS  Google Scholar 

  28. Vigouroux C, Maachi M, Nguyen TH, Coussieu C, Gharakhanian S, Funahashi T et al. Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. Aids 2003; 17: 1503–1511.

    Article  CAS  Google Scholar 

  29. Kannisto K, Sutinen J, Korsheninnikova E, Fisher RM, Ehrenborg E, Gertow K et al. Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy. Aids 2003; 17: 1753–1762.

    Article  CAS  Google Scholar 

  30. Park YW, Heymsfield SB, Gallagher D . Are dual-energy X-ray absorptiometry regional estimates associated with visceral adipose tissue mass? Int J Obes Relat Metab Disord 2002; 26: 978–983.

    Article  Google Scholar 

  31. Kamel EG, McNeill G, Han TS, Smith FW, Avenell A, Davidson L et al. Measurement of abdominal fat by magnetic resonance imaging, dual-energy X-ray absorptiometry and anthropometry in non-obese men and women. Int J Obes Relat Metab Disord 1999; 23: 686–692.

    Article  CAS  Google Scholar 

  32. Snijder MB, Visser M, Dekker JM, Seidell JC, Fuerst T, Tylavsky F et al. The prediction of visceral fat by dual-energy X-ray absorptiometry in the elderly: a comparison with computed tomography and anthropometry. Int J Obes Relat Metab Disord 2002; 26: 984–993.

    Article  CAS  Google Scholar 

  33. Cotter BR, Torriani FJ . Cardiovascular effects of antiretroviral therapy and noninvasive assessments of cardiovascular disease in HIV infection. Cardiovasc Toxicol 2004; 4: 281–286.

    Article  CAS  Google Scholar 

  34. Johnson JA, Albu JB, Engelson ES, Fried SK, Inada Y, Ionescu G et al. Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. Am J Physiol Endocrinol Metab 2004; 286: E261–E271.

    Article  CAS  Google Scholar 

  35. Lihn AS, Richelsen B, Pedersen SB, Huagaard SB, Rathje GS, Madsbad S et al. Increased expression of TNF-alpha, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels. Am J Physiol Endocrinol Metab 2003; 285: E1072–E1080.

    Article  CAS  Google Scholar 

  36. Reitman ML . Metabolic lessons from genetically lean mice. Annu Rev Nutr 2002; 22: 459–482.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients for their participation in this study. We also acknowledge Ruth Rousing, Hanne Willumsen, Lene Pors and Bente Baadegaard for excellent technical help. The study was supported by the Danish Medical Research Council (22-01-0019), the Danish National Research Foundation, the Danish AIDS Foundation and the United States Public Health Service (P01 HL28481).

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, The Centre of Inflammation and Metabolism, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark

    B Lindegaard, L F Larsen, A-B E Hansen, J Gerstoft & B K Pedersen

  2. The Copenhagen Muscle Research Centre, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark

    B Lindegaard, L F Larsen & B K Pedersen

  3. Departments of Human Genetics and Medicine at the David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    K Reue

Authors
  1. B Lindegaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L F Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A-B E Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Gerstoft
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B K Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Reue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Reue.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindegaard, B., Larsen, L., Hansen, AB. et al. Adipose tissue lipin expression levels distinguish HIV patients with and without lipodystrophy. Int J Obes 31, 449–456 (2007). https://doi.org/10.1038/sj.ijo.0803434

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803434

Keywords

This article is cited by

Search

Advanced search

Quick links