Endocrinology Vol. 145, No. 2 484-486
Copyright © 2004 by The Endocrine Society
Adiponectin and HIV-Lipodystrophy: Taking HAART
William B. Kinlaw and
Bryan Marsh
Department of Medicine Divisions of Endocrinology (W.B.K.) and Infectious Disease (B.M.) and the Norris Cotton Cancer Center (W.B.K.), Dartmouth Medical School, Lebanon, New Hampshire 03756
Address all correspondence and requests for reprints to: William B. Kinlaw, M.D., 606 Rubin Building, 1 Medical Center Drive, Lebanon, New Hampshire 03756. E-mail: William.kinlaw{at}hitchcock.org.
 |
The Problem
|
|---|
Infection with HIV and consequent AIDS is a major public health problem affecting more than 40 million people worldwide. Successful combination therapy based on HIV protease inhibitors, reverse transcriptase inhibitors (both nucleoside analogs and nonnucleoside analogs), and fusion inhibitors, with the goal of complete suppression of viral replication and meaningful immune restoration [highly active antiretroviral therapy (HAART)], has improved the prognosis of patients to the point that long-term complications of treatment have become an important clinical concern. Such major complications that have emerged are metabolic and have been termed the "HIV-lipodystrophy syndrome," although it is not clear that all of the described metabolic abnormalities are truly part of a single syndrome. These metabolic abnormalities were first associated with protease inhibitors, but both nonnucleoside analogs and at least one of the nucleoside analogs (stavudine) have also been implicated. The picture includes lipodystrophy, hypertriglyceride- and cholesterol-emia, and insulin resistance, with or without hyperglycemia (1, 2). This raises two major concerns. First is the specter of increased risk for cardiovascular disease, which could mitigate the prospect of longevity offered by HAART. Second is that cosmetic aspects as well as heightened concern about cardiovascular disease could impel patients to reject effective therapy. In this issue of Endocrinology, Xu et al. (3) describe a promising therapeutic approach in a mouse model of HIV-lipodystrophy.
|
The Syndrome
|
|---|
The lipodystrophy includes both the loss of facial and limb fat and central obesity, one or both of which may occur in a given individual (2). Atrophic adipose tissue contains small, poorly developed adipocytes and striking alterations in gene expression (see What Mechanism Might Underlie these Effects?) (4). The prevalence of lipodystrophy in patients on HAART is approximately 40% (2). Lipid levels are differentially affected by HIV-protease inhibitors, with ritonovir producing the most pronounced elevations. In a Swiss study, ritonavir caused increases in low-density lipoprotein cholesterol (50%), fasting triglycerides (201%), and, unexpectedly, Lp(a) (88%) (1). Frank diabetes is much more prevalent in HIV subjects with lipodystrophy than in those without it (5). Lipodystrophy patients have a 2-fold reduction in insulin sensitivity in clamp studies, and muscle is the primary locus of the defect (6). These alarming metabolic derangements, coupled with inflammatory markers related to AIDS per se, fuel concerns regarding cardiovascular risk from HAART, and raise the general hypothesis that a hormonal disturbance underlies them. Similarities between HIV lipodystrophy and Cushing’s syndrome suggested excess glucocorticoid action, but this has not been found (7). Investigative focus on hormones that are secreted from adipose tissue to influence caloric intake and disposition (adipocytokines) has produced intriguing clues, however. Among these, adiponectin has been implicated most convincingly in HIV lipodystrophy.
|
What Is Adiponectin?
|
|---|
Adiponectin is a peptide hormone secreted from adipocytes (8), and blood levels correlate with adipose content (9, 10). Two typical seven-transmembrane domain-type receptors (AdipoR1 and -R2) have been cloned (11). AdipoR1 predominates in muscle, whereas AdipoR2 is mostly hepatic. Administration of adiponectin to mice enhances fatty acid oxidation by muscle (12) and augments insulin action in the liver (13). Importantly, giving adiponectin to mice with insulin resistance associated with lipoatrophy or obesity improved insulin action and reduced lipid levels (14). On the other hand, adiponectin -/- mice exhibit insulin resistance and glucose intolerance (10) as well as evidence of vascular disease (15). Adiponectin levels are low in type II diabetics and are lower still in the subgroup with coronary artery disease (16). Peroxisome proliferator-activated receptor-
transduces signals for genes that govern adipocyte differentiation and insulin-induced metabolic alterations (17). Thiazolidinediones, synthetic peroxisome proliferator-activated receptor- agonists that are useful in the treatment of diabetes, enhance the expression of adiponectin in obese mice (18) and in type II diabetic patients (19). Similar effects are seen in normal subjects, obese or not (20). Adiponectin is unique among hormones in that it acts primarily to promote the efficient action of another hormone, namely insulin.
|
Adiponectin and HAART
|
|---|
Correlative studies have implicated adiponectin in the HIV-lipodystrophy syndrome. Adiponectin levels in HIV-infected men with lipodystrophy are approximately 50% of those without lipodystrophy, and approximately 25% of those in uninfected controls (21). Adiponectin, but not leptin, correlates with insulin sensitivity, and the abnormal metabolic parameters in a plethora of recent studies (21, 22, 23, 24), including one that showed reduced adiponectin mRNA in dystrophic fat (25). In this issue of Endocrinology, Xu et al. (3) directly address the hypothesis that adiponectin participates in the pathogenesis of the HIV-lipodystrophy syndrome by intervening in a mouse model. Administration of protease inhibitors caused a dose- and compound-related reduction in adiponectin and its mRNA in cultured fat cells in proportion to the propensity of each drug to produce lipodystrophy (ritonavir > indinavir > nelfinavir), and ritonavir also reduced adiponectin levels in mice. The mice also showed increased triglycerides and fatty acids, and enhanced hepatic fatty acid and cholesterol synthesis, thus simulating in the dyslipidemia associated with HAART in patients. Xu et al. (3) advanced beyond the correlative level by administering adiponectin to the mice. In their words, "a major novel finding of our present studies is that adiponectin replacement therapy can improve dyslipidemia induced by ritonavir." This was manifest by reduced serum levels of triglyceride and fatty acids, associated with commensurate reversal of accelerated hepatic synthesis. Cholesterol metabolism, however, was unaffected.
|
What Mechanism Might Underlie these Effects?
|
|---|
The HIV-lipodystrophy phenotype suggests a defect in both the control of adipocyte differentiation and lipid metabolism. Sterol response element-binding protein-1c (SREBP-1c, also known as adipocyte determination- and differentiation-dependent factor 1) plays a prominent role in both arenas (26, 27). SREBP-1c is an unusual transcription factor in that it is tethered to the endoplasmic reticulum by a hydrophobic tail. Proteolytic removal of the tail releases active SREBP-1c, which may travel to the nucleus, bind to DNA, and activate genes involved in long chain fatty acid synthesis and adipocyte differentiation (reviewed in Ref. 28). Activation of SREBP-1 is mediated by insulin (29). Recent microarray analysis showed that SREBP influences a wide spectrum of genes involved in the production of fatty acids. Indeed, mice overexpressing an active SREBP-1c exhibit peripheral lipoatrophy, severe insulin resistance, and hypertrigyceridemia, as is seen in patients taking HAART (30).
Effects of HIV protease inhibitors on SREBP have been studied in mice and in humans. In mice, ritonavir causes hypertriglyceridemia, hypercholesterolemia, and fatty liver, with enhanced rates of hepatic sterol and fatty acid synthesis. This is associated with increased nuclear accumulation of active SREBPs in liver and fat cells, and reduced SREBP clearance via an HIV-protease inhibitor-sensitive proteosomal pathway appears to be the mechanism (31). Likewise, analysis of peripheral adipose tissue from patients receiving HAART shows increased SREBP-1c content despite a 93% reduction in SREBP-1c mRNA, again indicating marked stabilization of the protein (4). Thus, in addition to reducing the production of adiponectin, HAART may enhance the action of the critical transcription factor SREBP-1c, leading to increased fatty acid synthesis by activating genes in the liver. Moreover, SREBP excess induces morphological abnormalities in adipose depots, as seen in the SREBP-1c transgenic mice (30).
HIV lipodystrophy syndrome is therefore a situation of reduced overall insulin action because of adiponectin deficiency, whereas lipogenesis, normally driven by insulin, is paradoxically enhanced because of SREBP-1c accumulation. Presumably both effects are ultimately related to the inhibition of proteosome function by the HIV drugs. Importantly, the findings of Xu et al. (3) indicate that adiponectin replacement therapy may functionally trump any direct effect of ritonavir on hepatic SREBP degradation pathways. The staging of a debate as to whether antiretroviral therapy should be modified based on cardiovascular risk at the recent International AIDS Conference highlights the practical challenge posed by the HIV-lipodystrophy syndrome (32). If further investigation confirms the utility of adiponectin replacement therapy, it will be reasonable to undertake trials in patients taking HAART, and in other insulin-resistant states as well.
|
Footnotes
|
|---|
Abbreviations: AdipoR1 and -R2, Two typical seven-transmembrane domain-type receptors; HAART, highly active antiretroviral therapy; SREBP-1c, sterol response element-binding protein-1c.
Received November 7, 2003.
Accepted for publication November 11, 2003.
|
References
|
|---|
- Periard D, Telenti A, Sudre P, Chesaux J, Halfon P, Reymond M, Marcovina S, Glauser M, Nicod P, Darioli R, Mooser V 1999 Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. Circulation 100:700–705[Abstract/Free Full Text]
- Chen D, Anoop M, Garg A 2002 Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 87:4845–4856[Abstract/Free Full Text]
- Xu A, Yin S, Wong L, Chan K, Lam K 2004 Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice. Endocrinology 145:487–494[Abstract/Free Full Text]
- Bastard J, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, Luboinski J, Laville M, Maachi M, Girard P, Rozenbaum W, Levan P, Capeau J 2002 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 359:1026–1031[CrossRef][Medline]
- Vigouroux C, Gharakhanian S, Salhi Y, Nguyen T, Chevenne D, Capeau J, Rozenbaum W 1999 Diabetes, insulin resistance and dyslipidemia in lipodystophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metab 25:225–232[Medline]
- Mynarcik D, McNurlan M, Steigbigel R, Fuhrer J, Gelato M 2000 Association of severe insulin resistance with both loss of limb fat and elevated tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 25:312–321
- Yanovski J, Miller K, Kino T, Friedman T, Chrousos G, Tsigos C, Faloon J 1999 Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. J Clin Endocrinol Metab 84:1925–1931[Abstract/Free Full Text]
- 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[CrossRef][Medline]
- Matsubara K, Maruoka S, Katayose S 2002 Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 147:173–180[Abstract]
- Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T 2002 Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci 103:137–142[Medline]
- Yamauchi T, Kamon J, Ito Y, Tschida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno N, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T 2003 Cloning of adiponectin receptors that mediate antidiabetic effects. Nature 423:762–769[CrossRef][Medline]
- Freubis J, Tsao T, Javorschi S, Ebbets-Reed D, Erickson M, Yen F, Bihain B, Lodish H 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010[Abstract/Free Full Text]
- Berg A, Combs T, Du X, Brownlee M, Scherer P 2001 The adipocyte-secreted protein ACRP30 enhances hepatic insulin action. Nat Med 7:947–953[CrossRef][Medline]
- Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akunama Y, Gavrilova O, Vinson C, Reitman M, Kagechika H, Shudo K, Yoda M, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946[CrossRef][Medline]
- Maeda N, Shimomura I, Kashida K, Nishizawa H, Matsuda M, Nagaratani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuru R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y 2002 Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737[CrossRef][Medline]
- Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuta M, Okamato Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Managuchi M, Ohmoto Y, Nakamura T, Yamashita T, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
- Spiegelman B, Flier J 1996 Adipogenesis and obesity: rounding out the big picture. Cell 87:377–389[CrossRef][Medline]
- Combs T, Wagner J, Berger J, Doebber T, Wang W, Zhang B, Tanen M, Berg A, O’Rahilly S, Savage D, Chatterjee K, Weiss S, Larson P, Gottesdiener K, Gertz B, Charron M, Scherer P, Moller D 2002 Induction of adipocyte complement related protein of 30 kilodaltons by PPAR- agonists: a potential mechanism of insulin sensitization. Endocrinology 143:998–1007[Abstract/Free Full Text]
- Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang J, Chen C, Chuang L 2002 Synthetic peroxisome proliferator-activated receptor- agonist, rosigltizone, increases plasma levels of adiponectin in type 2 diabetic subjects. Diabetes Care 25:376–380[Abstract/Free Full Text]
- Yu J, Javorschi S, Hevener A, Kruszynska Y, Norman R, Sinha M, Olefsky J 2002 The effect of thiazolidinedione on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968–2974[Abstract/Free Full Text]
- Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R 2003 Adipocyte-derived hormone levels in HIV lipodystrophy. Antiviral Ther 8:9–15[Medline]
- Vigouroux C, Maachi M, Nguyen T, Coussieu C, Gharakhanian S, Funahashi T, Matsuzawa Y, Shimomura I, Rozenbaum W, Capeau J, Bastard J 2003 Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS 17:1503–1511[CrossRef][Medline]
- Tong O, Sankale J, Hadigan C, Tan G, Rosenberg E, Kanki P, Grinspoon S, Hotamisligil G 2003 Regulation of adiponectin in human immunodeficency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab 88:1559–1564[Abstract/Free Full Text]
- Addy C, Gavrila A, Tsiodras S, Brodovicz K, Karchmer A, Mantzoros C 2003 Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab 88:627–636[Abstract/Free Full Text]
- Sutinen J, Korsheninnikova E, Funahashi T, Matsuzawa Y, Nyman T, Yki-Jarvinen H 2003 Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy. J Clin Endocrinol Metab 88:1907–1910[Abstract]
- Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS 1993 SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75:187–197[CrossRef][Medline]
- Tontonoz P, Kim J, Reed G, Spiegelman B 1993 ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol Cell Biol 13:4753–4759[Abstract/Free Full Text]
- Brown MS, Goldstein JL 1997 The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340[CrossRef][Medline]
- Yabe D, Komuro R, Liang G, Goldstein J, Brown M 2003 Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc Natl Acad Sci USA 100:3155–3160[Abstract/Free Full Text]
- Shimomura I, Hammer R, Richardson J, Ikemoto S, Basmakov Y, Goldstein J, Brown M 1998 Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194[Abstract/Free Full Text]
- Riddle T, Kuhel D, Wollett L, Fichtenbaum C, Hui D 2001 HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissue due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem 276:37514–37519[Abstract/Free Full Text]
- Cooper D, van der Valk M, Bozzette S, Should we modify antiretroviral treatment based on cardiovascular risk? Program of the 2nd International Aids Society Conference on HIV Pathogenesis and Treatment. Pairs, France, 2003 (Session 18)
This article has been cited by other articles:
|
|
|
|
 
J. E. Mallewa, E. Wilkins, J. Vilar, M. Mallewa, D. Doran, D. Back, and M. Pirmohamed
HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options
J. Antimicrob. Chemother.,
October 1, 2008;
62(4):
648 - 660.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Zink, J. Uhrlaub, J. DeWitt, T. Voelker, B. Bullock, J. Mankowski, P. Tarwater, J. Clements, and S. Barber
Neuroprotective and Anti-Human Immunodeficiency Virus Activity of Minocycline
JAMA,
April 27, 2005;
293(16):
2003 - 2011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Vernochet, S. Azoulay, D. Duval, R. Guedj, F. Cottrez, H. Vidal, G. Ailhaud, and C. Dani
Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines
J. Biol. Chem.,
January 21, 2005;
280(3):
2238 - 2243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. E. Kershaw and J. S. Flier
Adipose Tissue as an Endocrine Organ
J. Clin. Endocrinol. Metab.,
June 1, 2004;
89(6):
2548 - 2556.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
The Problem
The Syndrome