Lipodystrophy in HIV 1-infected patients: Lessons for obesity research

International Journal of Obesity

Volumn 31, Issue 12, 2007, Pages 1763-1776

  Villarroya, F ^a   Domingo, P ^b   Giralt, M ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

^b HOSPITAL DE LA SANTA CREU I SANT PAU   (Spain)

Author keywords

Adipocyte; HIV; Inflammation; Lipodystrophy; Mitochondria

Indexed keywords

ANTIRETROVIRUS AGENT; CHEMOKINE; CYTOKINE; EFAVIRENZ; FATTY ACID DERIVATIVE; NELFINAVIR; PROTEINASE INHIBITOR; ROSIGLITAZONE; STAVUDINE; ZIDOVUDINE;

ADIPOSE TISSUE; CELL DIFFERENTIATION; CELL HETEROGENEITY; CELL INFILTRATION; CLINICAL FEATURE; DRUG MECHANISM; DRUG WITHDRAWAL; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERLIPIDEMIA; INFLAMMATION; INSULIN RESISTANCE; LIPODYSTROPHY; LIPOMATOSIS; MACROPHAGE; MEDICAL RESEARCH; MITOCHONDRIAL MEMBRANE; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; TREATMENT RESPONSE;

ADIPOCYTES; ADIPOCYTES, BROWN; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; APOPTOSIS; CELL DIFFERENTIATION; DNA, MITOCHONDRIAL; HIV INFECTIONS; HIV-ASSOCIATED LIPODYSTROPHY SYNDROME; HUMANS; LIPOLYSIS; MITOCHONDRIA; OBESITY; TRANSCRIPTION FACTORS;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 36448962356     PISSN: 03070565     EISSN: 14765497     Source Type: Journal    
DOI: 10.1038/sj.ijo.0803698     Document Type: Review

References (136)

1. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352: 48-62.
2. Wohl DA, McComsey G, Tebas P, Brown TT, Glesby MJ, Reeds D et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006; 43: 645-653.
3. Gougeon ML, Penicaud L, Fromenty B, Leclercq P, Viard JP, Capeau J. Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Antivir Ther 2004; 9: 161-177.
4. Martin A, Mallon PW. Therapeutic approaches to combating lipoatrophy: do they work? J Antimicrob Chemother 2005; 55: 612-615.
5. Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, Kanki PJ et al. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab 2003; 88: 1559-1564.
6. Reitman ML, Arioglu E, Gavrilova O, Taylor SI. Lipoatrophy revisited. Trends Endocrinol Metab 2000; 11: 410-416.
7. 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.
8. Pacenti M, Barzon L, Favaretto F, Fincati K, Romano S, Milan G et al. Microarray analysis during adipogenesis identifies new genes altered by anti-retroviral drugs. AIDS 2006; 20: 1691-1705.
9. El Hadri K, Glorian M, Monsempes C, Dieudonne MN, Pecquery R, Giudicelli Y et al. In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J Biol Chem 2004; 279: 15130-15141.
10. Dowell P, Lane MD. C/EBPalpha reverses the anti-adipogenic effects of the HIV protease inhibitor nelfinavir. Biochem Biophys Res Commun 2005; 327: 571-574.
11. Caron M, Auclair M, Kronprobst M, Capeau J. Differential in vitro effects of indinavir, nelfinavir and amprenavir on cell differentiation, insulin sensivity and apoptosis in a adapted cell model: preventive impact of rosiglitazone. Antivir Ther 2001; 6: 17-18.
12. Jones SP, Janneh O, Back DJ, Pirmohamed M. Altered adipokine response in murine 3T3-F442A adipocytes treated with protease inhibitors and nucleoside reverse transcriptase inhibitors. Antivir Ther 2005; 10: 207-213.
13. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev 2000; 14: 1293-1307.
14. 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.
15. 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.
16. Mondal D, Larussa VF, Agrawal KC. Synergistic antiadipogenic effects of HIV type 1 protease inhibitors with tumor necrosis factor alpha: suppression of extracellular insulin action mediated by extracellular matrix-degrading proteases. AIDS Res Hum Retroviruses 2001; 17: 1569-1584.
17. Giralt M, Domingo P, Guallar JP, de la Concepcion ML, Alegre M, Domingo JC et al. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther 2006; 11: 729-740.
18. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106-1118.
19. Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003; 17: 1329-1338.
20. Pace CS, Martin AM, Hammond EL, Mamotte CD, Nolan DA, Mallal SA. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther 2003; 8: 323-331.
21. McComsey GA, Paulsen DM, Lonergan JT, Hessenthaler SM, Hoppel CL, Williams VC et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005; 19: 15-23.
22. Boyd MA, Carr A, Ruxrungtham K, Srasuebkul P, Bien D, Law M et al. Changes in body composition and mitochondrial nucleic acid content in patients switched from failed nucleoside analogue therapy to ritonavir-boosted indinavir and efavirenz. J Infect Dis 2006; 194: 642-650.
23. Walker UA, Auclair M, Lebrecht D, Kornprobst M, Capeau J, Caron M. Uridine abrogates the adverse effects of anti-retroviral pyrimidine analogues on adipose cell functions. Antivir Ther 2006; 11: 25-34.
24. Sutinen J, Walker AU, Sevastianova K, Klinker H, Häkkinen AM, Ristola M et al. Uridine supplementation for the treatment of anti-retroviral therapy-associated lipotrophy: a randomize, double-blind, placebo-controlled trial. Antivir Ther 2007; 12: 97-105.
25. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol 2003; 23: 1085-1094.
26. Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Considine RV et al. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 2004; 28: 176-179.
27. Dahlman I, Forsgren M, Sjogren A, Nordstrom EA, Kaaman M, Naslund E et al. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-{alpha}. Diabetes 2006; 55: 1792-1799.
28. Van Schothorst EM, Franssen-van Hal N, Schaap MM, Pennings J, Hoebee B, Keijer J. Adipose gene expression patterns of weight gain suggest counteracting steroid hormone synthesis. Obes Res 2005; 13: 1031-1041.
29. Gaou I, Malliti M, Guimont MC, Letteron P, Demeilliers C, Peytavin G et al. Effect of stavudine on mitochondrial genome and fatty acid oxidation in lean and obese mice. J Pharmacol Exp Ther 2001; 297: 516-523.
30. Kopecky J, Clarke G, Enerback S, Spiegelman B, Kozak LP. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest 1995; 96: 2914-2923.
31. Kopecky J, Hodny Z, Rossmeisl M, Syrovy I, Kozak LP. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution. Am J Physiol 1996; 270: E768-E775.
32. Carriere A, Fernandez Y, Rigoulet M, Penicaud L, Casteilla L. Inhibition of preadipocyte proliferation by mitochondrial reactive oxygen species. FEBS Lett 2003; 550: 163-167.
33. Carriere A, Carmona MC, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L et al. Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. J Biol Chem 2004; 279: 40462-40469.
34. Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 2006; 49: 784-791.
35. Rossmeisl M, Flachs P, Brauner P, Sponarova J, Matejkova O, Prazak T et al. Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores. Int J Obes Relat Metab Disord 2004; 28: S38-S44.
36. Villena JA, Viollet B, Andreelli F, Kahn A, Vaulont S, Sul HS. Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. Diabetes 2004; 53: 2242-2249.
37. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429: 771-776.
38. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761.
39. Chevillotte E, Giralt M, Miroux B, Ricquier D, Villarroya F. Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 2007; 56: 1042-1050.
40. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784-1792.
41. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. 'Buffalo hump' in men with HIV-1 infection. Lancet 1998; 351: 867-870.
42. Saint-Marc T, Touraine JL. 'Buffalo hump' in HIV-1 infection. Lancet 1998; 352: 319-320.
43. Fessel WJ, Follansbee SB, Barker B. Ultrastructural findings consistent with brown adipocytes in buffalo humps of HIV-positive patients with fat redistribution syndrome. Antivir Ther 2000; 5: 25.
44. Guaraldi G, De Fazio D, Orlando G, Murri R, Wu A, Guaraldi P et al. Facial lipohypertrophy in HIV-infected subjects who underwent autologous fat tissue transplantation. Clin Infect Dis 2005; 40: 13-15.
45. Rodriguez de la Concepcion ML, Domingo JC, Domingo P, Giralt M, Villarroya F. Uncoupling protein 1 gene expression implicates brown adipocytes in highly active anti-retroviral therapy-associated lipomatosis. AIDS 2004; 18: 959-960.
46. Rodriguez de la Concepcion ML, Guallar JP, Yubero P, Domingo JC, Alegre M, Iglesias R et al. Role of disturbances of brown with respect to white adipocyte biology an HAART- associated lipodystrophy and lipomatosis: studies in vitro and in vivo. Antivir Ther 2005; 10: L19.
47. Hansen JB, Jorgensen C, Petersen RK, Hallenborg P, De Matteis R, Boye HA et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc Natl Acad Sci USA 2004; 101: 4112-4117.
48. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277-359.
49. Vila MR, Gamez J, Solano A, Playan A, Schwartz S, Santorelli FM et al. Uncoupling protein-1 mRNA expression in lipomas from patients bearing pathogenic mitochondrial DNA mutations. Biochem Biophys Res Commun 2000; 278: 800-802.
50. Guallar JP, Vila MR, Lopez-Gallardo E, Solano A, Domingo JC, Gamez J et al. Altered expression of master regulatory genes of adipogenesis in lipomas from patients bearing tRNA(Lys) point mutations in mitochondrial DNA. Mol Genet Metab 2006; 89: 283-285.
51. Urso R, Gentile M. Are 'buffalo hump' syndrome, Madelung's disease and multiple symmetrical lipomatosis variants of the same dysmetabolism? AIDS 2001; 15: 290-291.
52. Mallon PW, Wand H, Law M, Miller J, Cooper DA, Carr A, HIV Lipodystrophy Case Definition Study; Australian Lipodystrophy Prevalence Survey Investigators. Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia. J Acquir Immune Defic Syndr 2005; 38: 156-162.
53. Rodriguez de la Concepcion ML, Yubero P, Domingo JC, Iglesias R, Domingo P, Villarroya F et al. Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Antivir Ther 2005; 10: 515-526.
54. Cinti S. The role of brown adipose tissue in human obesity. Nutr Metab Cardiovasc Dis 2006; 16: 569-574.
55. Oberkofler H, Dallinger G, Liu YM, Hell E, Krempler F, Patsch W. Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans. J Lipid Res 1997; 38: 2125-2133.
56. Yang X, Enerback S, Smith U. Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obes Res 2003; 11: 1182-1191.
57. Laplante M, Festuccia WT, Soucy G, Gelinas Y, Lalonde J, Berger JP et al. Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism. Diabetes 2006; 55: 2771-2778.
58. Hondares E, Mora O, Yubero P, Rodriguez de la Concepcion M, Iglesias R, Giralt M et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 2006; 147: 2829-2838.
59. Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005; 54: 1392-1419.
60. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007 1 May [E-pub ahead of print].
61. Miller J, Carr A, Emery S, Law M, Mallal S, Baker D et al. HIV lipodystrophy: prevalence, severity and correlates of risk in Australia. HIV Med 2003; 4: 293-301.
62. Palella Jr FJ, Cole SR, Chmiel JS, Riddler SA, Visscher B, Dobs A et al. Anthropometrics and examiner-reported body habitus abnormalities in the multicenter AIDS cohort study. Clin Infect Dis 2004; 38: 903-907.
63. Lopez S, Garrabou G, Martinez E, Domingo P, Fontdevila J, Gatell JM et al. Mitochondrial studies in adipose tissue of HIV-infected patients without fat redistribution. Antivir Ther 2004; 9: L20.
64. Jan V, Cervera P, Maachi M, Baudrimont M, Kim M, Vidal H et al. Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir Ther 2004; 9: 555-564.
65. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1989; 86: 27-31.
66. Peck MD, Mantero-Atienza E, Miguez-Burbano MJ, Lu Y, Fletcher MA, Shor-Posner G et al. The esterified plasma fatty acid profile is altered in early HIV-1 infection. Lipids 1993; 28: 593-597.
67. Van der Valk M, Reiss P, van Leth FC, Ackermans MT, Endert E, Romijn JA et al. Highly active anti-retroviral therapy-induced lipodystrophy has minor effects on human immunodeficiency virus-induced changes in lipolysis, but normalizes resting energy expenditure. J Clin Endocrinol Metab 2002; 87: 5066-5071.
68. Hazan U, Romero IA, Cancello R, Valente S, Perrin V, Mariot V et al. Human adipose cells express CD4, CXCR4, and CCR5 (corrected) receptors: a new target cell type for the immunodeficiency virus-1? FASEB J 2002; 16: 1254-1256.
69. Dupin N, Buffet M, Marcelin AG, Lamotte C, Gorin I, Ait-Arkoub Z et al. HIV and anti-retroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. AIDS 2002; 16: 2419-2424.
70. Munier S, Borjabad A, Lemaire M, Mariot V, Hazan U. In vitro infection of human primary adipose cells with HIV-1: a reassessment. AIDS 2003; 17: 2537-2539.
71. Maurin T, Saillan-Barreau C, Cousin B, Casteilla L, Doglio A, Penicaud L. Tumor necrosis factor-alpha stimulates HIV-1 production in primary culture of human adipocytes. Exp Cell Res 2005; 304: 544-551.
72. Noursadeghi M, Katz DR, Miller RF. HIV-1 infection of mononuclear phagocytic cells: the case for bacterial innate immune deficiency in AIDS. Lancet Infect Dis 2006; 6: 794-804.
73. Kino T, Chrousos GP. Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/ lipodystrophy syndrome? Ann NY Acad Sci 2004; 1024: 153-167.
74. Pugliese A, Vidotto V, Beltramo T, Petrini S, Torre D. A review of HIV-1 Tat protein biological effects. Cell Biochem Funct 2005; 23: 223-227.
75. Kino T, De Martino MU, Charmandari E, Ichijo T, Outas T, Chrousos GP. HIV-1 accessory protein Vpr inhibits the effect of insulin on the Foxo subfamily of forkhead transcription factors by interfering with their binding to 14-3-3 proteins: potential clinical implications regarding the insulin resistance of HIV-1-infected patients. Diabetes 2005; 54: 23-31.
76. Balasubramanyam A, Mersmann H, Jahoor F, Phillips TM, Sekhar RV, Schubert U et al. Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice. Am J Physiol Endocrinol Metab 2007; 292: E40-E48.
77. Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM et al. Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism. Cell Death Differ 2005; 12 (Suppl 1): 962-970.
78. Khanna N, Sirka C, Gupta S, Singh M. Lipodystrophy following hepatitis infection: a causative relationship? J Eur Acad Dermatol Venereol 2004; 18: 345-346.
79. Zylberberg H, Nalpas B, Pol S, Brechot C, Viard JP. Is there a relationship between hepatitis C virus infection and anti-retroviral-associated lipoatrophy? AIDS 2000; 14: 2055.
80. Duong M, Petit JM, Piroth L, Grappin M, Buisson M, Chavanet P et al. Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing anti-retroviral therapy. J Acquir Immune Defic Syndr 2001; 27: 245-250.
81. Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (London) 2005; 29: 281-286.
82. Greenway F. Virus-induced obesity. Am J Physiol Regul Integr Comp Physiol 2006; 290: R188-R189.
83. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew GF, Cook ME, Atkinson RL. Increased adiposity in animals due to a human virus. Int J Obes Relat Metab Disord 2000; 24: 989-996.
84. Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV. A human adenovirus enhances preadipocyte differentiation. Obes Res 2004; 12: 770-777.
85. Lindegaard B, Hansen AB, Pilegaard H, Keller P, Gerstoft J, Pedersen BK. Adipose tissue expression of IL-18 and HIV-associated lipodystrophy. AIDS 2004; 18: 1956-1986.
86. 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.
87. Lihn AS, Richelsen B, Pedersen SB, Haugaard 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.
88. Christeff N, De Truchis P, Melchior JC, Perronne C, Gougeon ML. Longitudinal evolution of HIV-1-associated lipodystrophy is correlated to serum cortisol:DHEA ratio and IFN-alpha. Eur J Clin Invest 2002; 32: 775-784.
89. Domingo P, Matias-Guiu X, Pujol RM, Francia E, Lagarda E, Sambeat MA et al. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 1999; 13: 2261-2267.
90. Lagathu C, Bastard JP, Auclair M, Maachi M, Kornprobst M, Capeau J et al. Anti-retroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro. Antivir Ther 2004; 9: 911-920.
91. Chi D, Henry J, Kelley J, Thorpe R, Smith JK, Krishnaswamy G. The effects of HIV infection on endothelial function. Endothelium 2000; 7: 223-242.
92. Laurence J, Mitra D, Steiner M, Staiano-Coico L, Jaffe E. Plasma from patients with idiopathic and human immunodeficiency virus-associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells. Blood 1996; 87: 3245-3254.
93. Shankar SS, Dube MP. Clinical aspects of endothelial dysfunction associated with human immunodeficiency virus infection and anti-retroviral agents. Cardiovasc Toxicol 2004; 4: 261-269.
94. Park IW, Wang JF, Groopman JE. HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes. Blood 2001; 97: 352-358.
95. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006; 74: 443-477.
96. Domingo P, Vidal F, Domingo JC, Veloso S, Sambeat MA, Torres F et al. Tumour necrosis factor alpha in fat redistribution syndromes associated with combination anti-retroviral therapy in HIV-1-infected patients: potential role in subcutaneous adipocyte apoptosis. Eur J Clin Invest 2005; 35: 771-780.
97. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 1994; 43: 1271-1278.
98. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111-1119.
99. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808.
100. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830.
101. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115-124.
102. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867.
103. Neels JG, Olefsky JM. Inflamed fat: what starts the fire? J Clin Invest 2006; 116: 33-35.
104. Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active anti-retroviral therapy. Metabolism 2002; 51: 1143-1147.
105. Hadigan C, Liebau J, Torriani M, Andersen R, Grinspoon S. Improved triglycerides and insulin sensitivity with 3 months of acipimox in human immunodeficiency virus-infected patients with hypertriglyceridemia. J Clin Endocrinol Metab 2006; 91: 4438-4444.
106. Janneh O, Hoggard PG, Tjia JF, Jones SP, Khoo SH, Maher B et al. Intracellular disposition and metabolic effects of zidovudine, stavudine and four protease inhibitors in cultured adipocytes. Antivir Ther 2003; 8: 417-426.
107. Ranganathan S, Kern PA. The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes. J Endocrinol 2002; 172: 155-162.
108. Van der Valk M, Allick G, Weverling GJ, Romijn JA, Ackermans MT, Lange JM et al. Markedly diminished lipolysis and partial restoration of glucose metabolism, without changes in fat distribution after extended discontinuation of protease inhibitors in severe lipodystrophic human immunodeficient virus-1-infected patients. J Clin Endocrinol Metab 2004; 89: 3554-3560.
109. Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK. Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 2004; 89: 5577-5582.
110. Gasic S, Tian B, Green A. Tumor necrosis factor alpha stimulates lipolysis in adipocytes by decreasing Gi protein concentrations. J Biol Chem 1999; 274: 6770-6775.
111. Haugaard SB, Andersen O, Pedersen SB, Dela F, Fenger M, Richelsen B et al. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy. Metabolism 2006; 55: 175-182.
112. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 2005; 25: 2062-2068.
113. Koutsari C, Jensen MD. Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity. J Lipid Res 2006; 47: 1643-1650.
114. Langin D, Arner P. Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. Trends Endocrinol Metab 2006; 17: 314-320.
115. Sorisky A, Magun R, Gagnon AM. Adipose cell apoptosis: death in the energy depot. Int J Obes Relat Metab Disord 2000; 24 (Suppl 4): S3-S7.
116. Prins JB, Niesler CU, Winterford CM, Bright NA, Siddle K, O'Rahilly S et al. Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes 1997; 46: 1939-1944.
117. Nelson-Dooley C, Della-Fera MA, Hamrick M, Baile CA. Novel treatments for obesity and osteoporosis: targeting apoptotic pathways in adipocytes. Curr Med Chem 2005; 12: 2215-2225.
118. Kim HK, Della-Fera M, Lin J, Baile CA. Docosahexaenoic acid inhibits adipocyte differentiation and induces apoptosis in 3T3-L1 preadipocytes. J Nutr 2006; 136: 2965-2969.
119. Weaver JG, Tarze A, Moffat TC, Lebras M, Deniaud A, Brenner C et al. Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. J Clin Invest 2005; 115: 1828-1838.
120. Ben-Romano R, Rudich A, Etzion S, Potashnik R, Kagan E, Greenbaum U et al. Nelfinavir induces adipocyte insulin resistance through the induction of oxidative stress: differential protective effect of antioxidant agents. Antivir Ther 2006; 11: 1051-1060.
121. Lloreta J, Domingo P, Pujol RM, Arroyo JA, Baixeras N, Matias-Guiu X et al. Ultrastructural features of highly active antiretroviral therapy-associated partial lipodystrophy. Virchows Arch 2002; 441: 599-604.
122. Domingo P, Matias-Guiu X, Pujol RM, Domingo JC, Arroyo JA, Sambeat MA et al. Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apoptosis in patients with highly active anti-retroviral therapy-associated lipodystrophy. J Infect Dis 2001; 184: 1197-1201.
123. Villarroya F, Domingo P, Giralt M. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Trends Pharmacol Sci 2005; 26: 88-93.
124. Dagon Y, Avraham Y, Berry EM. AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes. Biochem Biophys Res Commun 2006; 340: 43-47.
125. Lagathu C, Eustace B, Frantz D, Gu Y, Bastard JP, Maachi M et al. PIs and NRTIs increase oxidative stress and proinflammatory cytokine and chemokine production in human and murine adipocytes and macrophages. Antivir Ther 2005; 10: L21.
126. Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 2005; 11: 797-803.
127. Birk RZ, Rubinstein M. IFN-alpha induces apoptosis of adipose tissue cells. Biochem Biophys Res Commun 2006; 345: 669-674.
128. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46: 2347-2355.
129. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351: 871-875.
130. Lafontan M, Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 2003; 24: 276-283.
131. Deveaud C, Beauvoit B, Salin B, Schaeffer J, Rigoulet M. Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes. Mol Cell Biochem 2004; 267: 157-166.
132. Deveaud C, Beauvoit B, Hagry S, Galinier A, Carriere A, Salin B et al. Site specific alterations of adipose tissue mitochondria in 3′-azido-3′-deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy? Biochem Pharmacol 2005; 70: 90-101.
133. Bruun JM, Lihn AS, Madan AK, Pedersen SB, Schiott KM, Fain JN et al. Higher production of IL-8 in visceral vs subcutaneous adipose tissue. Implication of nonadipose cells in adipose tissue. Am J Physiol Endocrinol Metab 2004; 286: E8-E13.
134. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145: 2273-2282.
135. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab 2005; 90: 2282-2289.
136. Dusserre E, Moulin P, Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 2000; 1500: 88-96.