Journal of Diabetes Research

Journal of Diabetes Research / 2012 / Article
Special Issue

Pathophysiological Insights into Cardiovascular Health in Metabolic Syndrome

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Review Article | Open Access

Volume 2012 |Article ID 103063 | 7 pages |

The Pathophysiology of HIV-/HAART-Related Metabolic Syndrome Leading to Cardiovascular Disorders: The Emerging Role of Adipokines

Academic Editor: Yingmei Zhang
Received05 Jul 2011
Accepted01 Nov 2011
Published08 Dec 2011


Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate metabolic syndrome (MS) associated with increased incidence of cardiovascular disorders. Characteristics of HIV infection, such as immunodeficiency, viral load, and duration of the disease, in addition to the highly active antiretroviral therapy (HAART) have been suggested to induce MS in these patients. It is well documented that MS involves a number of traditional cardiovascular risk factors, like glucose, lipids, and arterial blood pressure abnormalities, leading to extensive atherogenic arterial wall changes. Nevertheless, the above traditional cardiovascular risk factors merely explain the exacerbated cardiovascular risk in MS. Nowadays, the adipose-tissue derivatives, known as adipokines, have been suggested to contribute to chronic inflammation and the MS-related cardiovascular disease. In view of a novel understanding on how adipokines affect the pathogenesis of HIV/HAART-related MS and cardiovascular complications, this paper focuses on the interaction of the metabolic pathways and the potential cardiovascular consequences. Based on the current literature, we suggest adipokines to have a role in the pathogenesis of the HIV/HAART-related MS. It is crucial to understand the pathophysiology of the HIV/HAART-related MS and apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients.

1. Introduction

Treatment with highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) has been documented to significantly increase life expectancy [1]. However, adverse metabolic effects like dyslipidemia, increased blood pressure, and insulin resistance have been attributed to HAART [2, 3]. Therefore, the use of HAART raises concerns regarding metabolic disorders and cardiovascular risk in HIV-infected patients who now present an extended life expectancy. An increase of approximately 26% of the risk for myocardial infarction has been reported in patients on HAART [4]. The detrimental effect of HAART on the arterial wall properties [58] has been proposed as an underlying mechanism, while it has been documented that HIV infection per se may promote atherosclerosis through immunodeficiency, chronic inflammation progress, viral load, and endothelial cell dysfunction, and either directly or indirectly via metabolic risk factors [913]. The exact pathophysiological events underlying the development of metabolic changes in HIV-infected patients are still under investigation. Several studies have identified specific defects in adipocyte function as main drivers in the pathogenesis of some of the metabolic changes in these patients. The list of adipocyte-secreted cytokines, known as adipokines, has been continuously expanded to include biomolecules, such as leptin, adiponectin, resistin, visfatin, apelin, acylation stimulating protein, omentin, and vaspin. In addition to this, TNF-α, adipose-derived interleukins, and acute-phase proteins have been also considered as adipokines by some researchers [14]. We should mention that the current terminology refers to a cytokine as an immunomodulating agent. Taking this into account, adiponectin, leptin, and resistin are not appropriately considered as adipokines, since they do not act on the immune system. Nevertheless, these peptides are still referred to as adipokines in the literature; however, they could be more accurately put into the larger, growing list of adipose-tissue-derived hormones. The role of those adipose-tissue-secreted hormones in the pathophysiology of HIV-/HAART-related metabolic syndrome (MS) in HIV-infected patients is still the subject of intense research. Therefore, we decided to review published data regarding the emerging role of adipokines in the increased cardiovascular risk in HIV-infected patients related to the HIV/HAART-associated MS. The main differences between the pathogenesis of MS in HIV-infected patients and other patients are summarized in Table 1.

HIV-infected patientsNon-HIV-infected patients

(A)HAART-induced dyslipidemia, hypertriglyceridemia, HDL reduction, especially if PI usedFat abnormal metabolism leading to hypertriglyceridemia and dyslipidemia

(B)HAART-induced leptin deficiency and hypoadiponectinemia leading to insulin resistanceHypoadiponectinemia leading to insulin resistance and abnormal glucose metabolism

(C)HIV-associated “lipodystrophy” syndrome—body fat abnormalities—fat accumulation around the neck, dorsocervical region as “buffalo hump,” abdomen, and trunkWaist circumference enlargement due to abdominal fat accumulation

2. Body Fat and Waist Circumference Abnormalities in HIV-Infected Patients

The prevalence of the HIV-associated “lipodystrophy” syndrome according to previous studies approaches 80% of patients receiving HAART [15], while other studies report only a prevalence of 17% [16]. Significant differences in “lipodystrophy” rates exist when comparing patients with or without HAART. In one of these studies the prevalence of any body change was 62% in protease inhibitor (PI)-experienced patients, 33% in PI-naive patients and 21% in antiretroviral-naive patients [17]. There seems to be a lower prevalence of morphological body shape and fat redistribution changes in HIV-infected children, while an increase in serum adipokine levels has been additionally described [18]. According to the European Paediatric Lipodystrophy Group, approximately a quarter of children and adolescents show signs of lipodystrophy, similar to those described in adults [19].

Lipoatrophy typically includes decreased subcutaneous fat in the upper or lower extremities with prominent veins, loss of buttock subcutaneous fat, and facial atrophy [20]. The fat wasting should be differentiated from other wasting conditions associated with HIV infection, including the AIDS-wasting syndrome, malnutrition, cachexia, adrenal insufficiency, and severe chronic infections.

Lipodystrophy is characterized by lipoatrophy/fat loss, lipohypertrophy/fat accumulation, or both [20]. Fat accumulation can be seen around the neck, the dorsocervical region as “buffalo hump,” the abdomen, and the trunk or as subcutaneous fat deposits, that is, lipomas, particularly in the dorsocervical area. These findings can be either symmetric or asymmetric. Breast enlargement has also been observed.

3. Dyslipidemia and Insulin Resistance in HIV-Infected Patients

The association of dyslipidemia with many antiretroviral regimens and especially PIs has been well established [21]. The effect on total cholesterol levels appears to be regimen dependent as shown in the Swiss HIV-1 Cohort Study [22]. Potential mechanisms for PI-associated dyslipidemia include (a) inhibition of sterol regulatory element-binding protein-1 (SREBP-1) activation in the liver and/or adipocytes along with the protease-mediated breakdown of apolipoprotein-B [23], (b) direct enhancement of the formation of very-low-density lipoproteins (VLDLs) [24] and the reduction of lipoprotein lipase activity [25], and (c) changes in the mobilization of lipid stores [26]. Nevertheless, lipid disorders can also occur during therapies not including PIs [27, 28]. Insulin resistance is also a significant metabolic side effect associated with HAART. PIs affect insulin sensitivity through various mechanisms such as IRS-1 phosphorylation and subsequent glucose uptake from adipocytes [29]. Lipodystrophy may also result in B-cell dysfunction [30] and is associated with impaired feedback of insulin on B-cells [31]. On the other hand, HIV-1 infection itself may be independently linked to the attenuation of insulin sensitivity. The HIV-1 accessory protein Vpr induces transcription of glucocorticoid-responsive promoters, in vitro, thus increasing sensitivity to glucocorticoids [32]. It also attenuates peroxisome-proliferator-activated receptor-γ (PPAR-γ) activity [33] and interferes with the suppressive effects of insulin on forehead transcription factors [34]. Therefore, it contributes to the tissue-selective insulin resistance. The end result of all the described factors is the attenuation of insulin sensitivity.

4. Parameters of HIV-/HAART-Induced Metabolic Syndrome and Cardiovascular Disorders

Concerning arterial stiffness, expressed by pulse wave velocity (PWV), and markers of metabolic profile, we recently compared HIV-infected patients age- and sex-matched individuals with either with hypertension or without any chronic disease [35]. In that study, HIV-infected patients had higher PWV levels than healthy controls, but lower than hypertensive patients. Notably, patients on HAART had similar PWV to hypertensive patients. In multivariate analysis, the independent determinants of increased arterial stiffness were HAART duration and MS parameters, like serum lipids and blood pressure.

In our previously published study, we performed a comparative evaluation of endothelial dysfunction between HIV-positive individuals and age- and sex-matched controls with similar risk factors and a group of patients with established coronary artery disease (CAD). HIV-infected patients presented endothelial dysfunction to a similar extent as patients with CAD. Moreover, HIV-infected patients taking PIs had higher blood pressure, cholesterol, and triglycerides than those not taking PIs. Importantly, endothelial dysfunction was associated with elevated serum triglycerides. Therefore, we concluded that HAART-induced hypertriglyceridemia might have been a plausible mechanism explaining endothelial dysfunction in HIV-infected individuals. In the same study, we found an increased carotid intima media thickness (IMT), an index of subclinical carotid atherosclerosis, in HIV-infected patients. Most importantly, carotid IMT levels were equivalent in HIV-infected and CAD groups. So, we suggested that subclinical carotid atherosclerosis was closely related to PI-related changes of metabolic parameters in HIV-infected patients.

Current recommendations by the National Cholesterol Education Program for HIV-infected persons focus on LDL-C levels, as the primary target of the lipid-lowering therapy. The LDL cholesterol goal has been set <160 mg/dL for persons with 0-1 cardiovascular risk factors, <130 mg/dL for persons with multiple (2+) risk factors, and <100 mg/dL for persons with established coronary heart disease (CHD) or CHD risk equivalents. After lifestyle modifications, statins should be used to lower LDL-C levels. Therapy with fibrates is recommended to lower triglycerides levels. However, omega-3 fatty acids can be effective means of triglycerides lowering as well, particularly in patients with markedly elevated triglycerides levels. The efficacy of statins in HIV-infected persons appears to be lower than expected, although adherence to statins therapy has not been well assessed. Statins combining high potency and minor interactions with antiretroviral therapy (pravastatin, fluvastatin, atorvastatin, and rosuvastatin) should be preferred as the initial therapy, though comparative studies in HIV-infected persons are scarce.

Adequate choice and dosing of lipid-lowering drugs, given as single agents or in combination therapy, and care for drug compliance in HIV-infected patients at moderate or high cardiovascular risk should help maximize their long-term health.

5. HIV-/HAART-Induced Metabolic Syndrome: The Role of Adipokines

Visceral adipose tissue (VAT) is the predominant adipose tissue compartment responsible for the production of adipokines. A growing body of evidence supports the emerging role of adipokines in metabolic homeostasis and atherosclerosis. In this paper, we have reviewed the recent progress regarding the role of adipokines in the HIV/HAART-induced MS and cardiovascular disease (CVD). A better understanding of the molecular mechanisms will lead to the discovery of new drugs and reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients receiving HAART.

5.1. Leptin

Leptin, which was the first adipokine identified, influences food intake through direct effects on the hypothalamus [36]. This adipocyte-derived hormone has actions in the brain (e.g., hypothalamus, cortex, and limbic areas) and in a number of peripheral tissues as well as cells of the pancreas, liver, and immune system. The central actions of leptin include energy and glucose homeostasis, reproductive functions, and immunity [37, 38]. The relationship between adiposity and leptin levels appears similar to controls and HIV infected but untreated patients [39]. On the other hand, severe lipodystrophy syndromes are characterized by loss of subcutaneous adipose tissue and a relative deficiency of leptin [40]. The effect of HAART on leptin levels is subject of controversy. In few studies, HAART administration had been associated with lipodystrophy and hypoleptinemia [41], while numerous studies had predominantly demonstrated no effect of HAART on leptin concentrations [42]. The above discrepancy was mainly attributed to the differential effects of HAART on fat-mass distribution and not directly to leptin per se [43]. Indeed, HAART without fat-mass re-distribution did not influence leptin levels [44]. Moreover, there is a weak correlation of leptin with insulin sensitivity in HIV-infected population [45].

Accumulating data support the proinflammatory and proatherogenic properties of leptin in either noninfected or HIV-infected patients [46, 47]. Although there is no prospective study evaluating the association of leptin with long-term cardiovascular events in HIV infected patients, the high levels of leptin in that population apparently increases the inflammatory milieu and perhaps the total cardiovascular risk. Future studies will elucidate the role of leptin in CVD progression in HIV-infected patients.

5.2. Adiponectin

Adiponectin, a well-studied adipokine, is secreted by fatty cells and is widely regarded to exert a counterregulatory role in atherogenesis, by its antioxidant, anti-inflammatory, antithrombotic, and direct anti-atherosclerotic properties [48]. Adiponectin expression is suppressed in patients with obesity and type 2 diabetes, showing an inverse relationship with insulin resistance and visceral adiposity [49]. Treatment-naïve, HIV-1-positive patients appear with suppressed adiponectin levels [50]. In previous studies, circulating adiponectin levels were suppressed in patients with chronic HIV infection and fat redistribution, but the underlying mechanisms remain obscure [51, 52]. Moreover, patients treated with HAART, especially those with lipodystrophy, showed gradual downregulation in adiponectin serum levels [53]. Notably, in the latter subgroup of patients, the HAART-induced hypoadiponectinemia was associated with accelerated cardiovascular impairment [54]. Taken all together, the suppression of adiponectin levels in HIV-infected patients under HAART may deteriorate numerous metabolic parameters (e.g., insulin resistance, lipid profile, etc.) leading to detrimental cardiovascular events.

5.3. Resistin

Despite the quite promising data from rodent studies, human data did not consistently confirm the association of resistin with insulin resistance, diabetes, and obesity [55]. Contrary to the aforementioned findings, elevated resistin levels have been found in HIV-infected patients compared to uninfected individuals. That difference was ascribed to HAART-related metabolic changes [56, 57]. Perhaps, HIV/HAART-related MS alters the regulatory mechanisms of resistin, but this hypothesis requires further investigation. On the other hand, the predominant sources of human resistin are macrophages and mononuclear leukocytes, and to a lesser extent, adipocytes [58]. Conditions of low-grade systemic inflammation, such as diabetes and atherosclerosis, may induce macrophage expression of resistin and increase circulating levels, independently of metabolic changes. The latter notion is also supported by the previously reported contributory role of resistin to pathologic processes, like inflammation, endothelial dysfunction, thrombosis, and smooth muscle cell dysfunction, leading to CVD [59]. Unambiguously, future studies will shed more light on the interplay between resistin and HIV/HAART-related MS and CVD.

5.4. Visfatin

Visfatin, also known as nicotinamide phosphoribosyltransferase (NAMPT), functions as a growth factor for early B cells within the immune system [60]. Although visfatin is expressed and regulated by the adipose tissue, its relationship with adiposity-related insulin resistance is controversial [61, 62]. Regarding the impact of HAART on visfatin, a single study demonstrated significantly increased serum visfatin levels after HAART initiation, along with insulin resistance augmentation, and without concomitant changes in fat mass [63]. Thus, the fluctuations of insulin resistance and glucose homeostasis in HIV-positive patients may explain the regulation of visfatin.

Importantly, patients with stable coronary and carotid disease appear with high circulating levels of visfatin [64, 65], while macrophages derived from human unstable carotid and coronary plaques increasingly express visfatin [66]. Future studies clarifying the involvement of proinflammatory visfatin in the HIV/HAART-associated MS may better define the cardiovascular risk.

5.5. Apelin

Apelin, an adipocyte-secreted factor, has been recently identified as a contributor to glucose homeostasis and insulin resistance [67]. Abundant expression of apelin and its receptor, APJ, has been detected in endothelial cells from large arteries and coronary blood vessels and in the heart [68]. Moreover, previous trials have suggested apelin as a potent regulator of cardiovascular function [69]. We and other investigators have recently documented the inverse relationship between circulating apelin levels and CHD [70, 71].

The interplay between apelin with HIV infection and initially reported by Zou et al. who described the inhibition of HIV-1 and HIV-2 entrance in CHO and NP-2 cells expressing CD4 and its receptor after preincubation with apelin [72]. Moreover, apelin receptor has been shown in vitro to act as HIV-1 coreceptor [73]. Taken together, more functional studies are required to determine the precise role of apelin/APJ in cardiovascular regulation, insulin resistance, and the susceptibility to HIV infection. This information would help to evaluate its potential as a future drug target.

5.6. Vaspin

A novel adipokine, vaspin, has been recently designated as a mediator of obesity, insulin resistance, and type 2 diabetes [74]. Both animal and clinical studies suggest that elevated vaspin levels in serum and adipose tissue may be a compensatory response to elevated insulin resistance, secondary to metabolic complications [75]. Extremely limited data implicate the association of low serum vaspin levels with atherosclerosis development and progression [64, 76]. Although vaspin exerts insulin-sensitizing and atheroprotective actions, its relationship with cardiovascular complications in HIV/HAART-related MS has not been investigated.

6. Conclusions

Adipokines appear to have a leading role in the pathogenesis of the HIV/HAART-related MS [77]. Leptin deficiency and hypoadiponectinemia, for example, correlate with insulin resistance and body fat abnormalities. These disorders affect the cardiovascular health of HIV patients through the amelioration of atherosclerosis and endothelial dysfunction. Furthermore, novel adipokines, such as visfatin, apelin, and vaspin, have emerged as potential mediators of the interplay between MS and atherosclerosis in HIV-infected patients. It is of great interest to study the pathological mechanism of the HIV/HAART-related MS and its cardiovascular complications and try to apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients.


AIDS:Acquired immunodeficiency syndrome
CHD:Coronary heart disease
CHO:Chinese hamster Ovary
CVD:Cardiovascular disease
HIV:Human immunodeficiency virus
HAART:Highly active antiretroviral therapy
IMT:Intima media thickness
LDL:Low-density lipoprotein
MS:Metabolic syndrome
NAMPT:Nicotinamide phosphoribosyltransferase
NNRTI:Non-nucleoside reverse transcriptase inhibitors
NP:Neural progenitors
NRTI:Nucleoside reverse transcriptase inhibitors
PI:Protease inhibitors
PPAR-γ:Peroxisome-proliferator-activated receptor-γ
PWV:Pulse wave velocity
SREBP:Sterol regulatory element-binding protein
TNF:Tumor necrosis factor
VAT:Visceral adipose tissue
VLDL:Very-low-density lipoprotein.


Nikolaos P. E. Kadoglou was awarded a grant by the Alexander S. Onassis Public Benefit Foundation.


  1. F. J. Palella Jr., K. M. Delaney, A. C. Moorman et al., “Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators,” Respiratory Care, vol. 43, no. 7, p. 544, 1998. View at: Google Scholar
  2. G. Guaraldi, C. Stentarelli, S. Zona et al., “Lipodystrophy and anti-retroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects,” Atherosclerosis, vol. 208, no. 1, pp. 222–227, 2010. View at: Publisher Site | Google Scholar
  3. S. Grinspoon and A. Carr, “Cardiovascular risk and body-fat abnormalities in HIV-infected adults,” The New England Journal of Medicine, vol. 352, no. 1, pp. 48–62, 2005. View at: Publisher Site | Google Scholar
  4. N. Friis-Moller, C. A. Sabin, and R. Weber, “Combination antiretroviral therapy and the risk of myocardial infarction,” The New England Journal of Medicine, vol. 349, no. 21, pp. 1993–2003, 2003. View at: Google Scholar
  5. M. Charakida, A. E. Donald, H. Green et al., “Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy,” Circulation, vol. 112, no. 1, pp. 103–109, 2005. View at: Publisher Site | Google Scholar
  6. P. Y. Hsue, P. W. Hunt, Y. Wu et al., “Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients,” AIDS, vol. 23, no. 15, pp. 2021–2027, 2009. View at: Publisher Site | Google Scholar
  7. J. Lekakis, S. Tsiodras, I. Ikonomidis et al., “HIV-positive patients treated with protease inhibitors have vascular changes resembling those observed in atherosclerotic cardiovascular disease,” Clinical Science, vol. 115, no. 5-6, pp. 189–196, 2008. View at: Publisher Site | Google Scholar
  8. C. M. Thomas and E. J. Smart, “How HIV protease inhibitors promote atherosclerotic lesion formation,” Current Opinion in Lipidology, vol. 18, no. 5, pp. 561–565, 2007. View at: Publisher Site | Google Scholar
  9. B. Coll, S. Parra, C. Alonso-Villaverde et al., “The role of immunity and inflammation in the progression of atherosclerosis in patients with HIV infection,” Stroke, vol. 38, no. 9, pp. 2477–2484, 2007. View at: Publisher Site | Google Scholar
  10. K. E. Mondy, “Determinants of endothelial function in human immunodeficiency virus infection: a complex interplay among therapy, disease, and host factors,” Journal of The Cardiometabolic Syndrome, vol. 3, no. 2, pp. 88–92, 2008. View at: Google Scholar
  11. R. C. Kaplan, L. A. Kingsley, S. J. Gange et al., “Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men,” AIDS, vol. 22, no. 13, pp. 1615–1624, 2008. View at: Publisher Site | Google Scholar
  12. D. Francisci, S. Giannini, F. Baldelli et al., “HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction,” AIDS, vol. 23, no. 5, pp. 589–596, 2009. View at: Publisher Site | Google Scholar
  13. P. Y. Hsue, P. W. Hunt, A. Schnell et al., “Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis,” AIDS, vol. 23, no. 9, pp. 1059–1067, 2009. View at: Publisher Site | Google Scholar
  14. P. Trayhurn and I. S. Wood, “Adipokines: inflammation and the pleiotropic role of white adipose tissue,” British Journal of Nutrition, vol. 92, no. 3, pp. 347–355, 2004. View at: Publisher Site | Google Scholar
  15. G. M. Behrens, M. Stoll, and R. E. Schmidt, “Lipodystrophy syndrome in HIV infection. What is it, what causes it and how can it be managed?” Drug Safety, vol. 23, no. 1, pp. 57–76, 2000. View at: Google Scholar
  16. C. Jerico, H. Knobel, M. Montero et al., “Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors,” Diabetes Care, vol. 28, no. 1, pp. 132–137, 2005. View at: Publisher Site | Google Scholar
  17. J. Miller, A. Carr, S. Emery et al., “HIV lipodystrophy: prevalence, severity and correlates of risk in Australia,” HIV Medicine, vol. 4, no. 3, pp. 293–301, 2003. View at: Publisher Site | Google Scholar
  18. S. Resino, D. Micheloud, R. Lorente, J. Bellon, M. Navarro, and M. Munoz-Fernandez, “Adipokine profiles and lipodystrophy in HIV-infected children during the first 4 years on highly active antiretroviral therapy,” HIV Medicine, vol. 12, no. 1, pp. 54–60, 2011. View at: Publisher Site | Google Scholar
  19. European Paediatric Lipodystrophy Group, “Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe,” AIDS, vol. 18, no. 10, pp. 1443–1451, 2004. View at: Publisher Site | Google Scholar
  20. M. K. Leow, C. L. Addy, and C. S. Mantzoros, “Clinical review 159—human immunodeficiency virus/highly active antiretroviral therapy-associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 5, pp. 1961–1976, 2003. View at: Publisher Site | Google Scholar
  21. N. Friis-Moller, R. Weber, P. Reiss et al., “Cardiovascular disease risk factors in HIV patients—association with antiretroviral therapy. Results from the DAD study,” AIDS, vol. 17, no. 8, pp. 1179–1193, 2003. View at: Publisher Site | Google Scholar
  22. D. Periard, A. Telenti, P. Sudre et al., “Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The swiss HIV cohort study,” Circulation, vol. 100, no. 7, pp. 700–705, 1999. View at: Google Scholar
  23. J. S. Liang, O. Distler, D. A. Cooper et al., “HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia,” Nature Medicine, vol. 7, no. 12, pp. 1327–1331, 2001. View at: Publisher Site | Google Scholar
  24. J. Q. Purnell, A. Zambon, R. H. Knopp et al., “Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects,” AIDS, vol. 14, no. 1, pp. 51–57, 2000. View at: Publisher Site | Google Scholar
  25. S. Ranganathan and P. A. Kern, “The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes,” Journal of Endocrinology, vol. 172, no. 1, pp. 155–162, 2002. View at: Publisher Site | Google Scholar
  26. D. N. Reeds, B. Mittendorfer, B. W. Patterson, W. G. Powderly, K. E. Yarasheski, and S. Klein, “Alterations in lipid kinetics in men with HIV-dyslipidemia,” American Journal of Physiology, vol. 285, no. 3 48-3, pp. E490–E497, 2003. View at: Google Scholar
  27. M. P. Dube, J. H. Stein, J. A. Aberg et al., “Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV medicine association of the infectious disease society of America and the adult AIDS clinical trials group,” Clinical Infectious Diseases, vol. 37, no. 5, pp. 613–627, 2003. View at: Publisher Site | Google Scholar
  28. F. Van Leth, P. Phanuphak, K. Ruxrungtham et al., “Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN study,” The Lancet, vol. 363, no. 9417, pp. 1253–1263, 2004. View at: Publisher Site | Google Scholar
  29. G. Meininger, C. Hadigan, M. Laposata et al., “Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution,” Metabolism, vol. 51, no. 2, pp. 260–266, 2002. View at: Publisher Site | Google Scholar
  30. O. Anderson, S. B. Haugaard, U. B. Andersen et al., “Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in β-cell function,” Metabolism, vol. 52, no. 10, pp. 1343–1353, 2003. View at: Publisher Site | Google Scholar
  31. S. B. Haugaard, O. Andersen, H. Storgaard et al., “Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of nonglucose secretagogues and insulin resistance of β-cells,” American Journal of Physiology, vol. 287, no. 4, pp. E677–E685, 2004. View at: Publisher Site | Google Scholar
  32. T. Kino, A. Gragerov, O. Slobodskaya, M. Tsopanomichalou, G. P. Chrousos, and G. N. Pavlakis, “Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators,” Journal of Virology, vol. 76, no. 19, pp. 9724–9734, 2002. View at: Publisher Site | Google Scholar
  33. S. Shrivastav, T. Kino, G. P. Chrousos, and J. B. Kopp, “HIV-1 Vpr binds and inhibits PPAR-gamma: implications for HIV-associated insulin resistance and lipodystroph,” in Proceedings of the International Meeting of the Institute of Human Virology, Baltimore, Md, USA, 2000. View at: Google Scholar
  34. T. Kino, M. U. De Martino, E. Charmandari, T. Ichijo, T. Outas, and G. P. Chrousos, “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, vol. 54, no. 1, pp. 23–31, 2005. View at: Publisher Site | Google Scholar
  35. J. Lekakis, I. Ikonomidis, J. Palios et al., “Association of highly active antiretroviral therapy with increased arterial stiffness in patients infected with human immunodeficiency virus,” American Journal of Hypertension, vol. 22, no. 8, pp. 828–834, 2009. View at: Publisher Site | Google Scholar
  36. J. M. Beasley, B. A. Ange, C. A. Anderson et al., “Characteristics associated with fasting appetite hormones (obestatin, ghrelin, and leptin),” Obesity, vol. 17, no. 2, pp. 349–354, 2009. View at: Google Scholar
  37. J. M. Beasley, B. A. Ange, C. A. Anderson, E. R. Miller, J. T. Holbrook, and L. J. Appel, “Characteristics associated with fasting appetite hormones (obestatin, Ghrelin, and Leptin),” Obesity, vol. 17, no. 2, pp. 349–354, 2009. View at: Publisher Site | Google Scholar
  38. K. Guo, J. E. McMinn, T. Ludwig et al., “Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities,” Endocrinology, vol. 148, no. 8, pp. 3987–3997, 2007. View at: Publisher Site | Google Scholar
  39. A. B. Dzwonek, V. Novelli, and A. Schwenk, “Serum leptin concentrations and fat redistribution in HIV-1-infected children on highly active antiretroviral therapy,” HIV Medicine, vol. 8, no. 7, pp. 433–438, 2007. View at: Publisher Site | Google Scholar
  40. E. A. Oral and J. L. Chan, “Rationale for leptin-replacement therapy for severe lipodystrophy,” Endocrine Practice, vol. 16, no. 2, pp. 324–333, 2010. View at: Google Scholar
  41. A. Calmy, A. Gayet-Ageron, F. Montecucco et al., “HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial,” AIDS, vol. 23, no. 8, pp. 929–939, 2009. View at: Google Scholar
  42. A. B. Dzwonek, V. Novelli, and A. Schwenk, “Serum leptin concentrations and fat redistribution in HIV-1-infected children on highly active antiretroviral therapy,” HIV Medicine, vol. 8, no. 7, pp. 433–438, 2007. View at: Publisher Site | Google Scholar
  43. E. Hammond, E. McKinnon, and D. Nolan, “Human immunodeficiency virus treatment-induced adipose tissue pathology and lipoatrophy: prevalence and metabolic consequences,” Clinical Infectious Diseases, vol. 51, no. 5, pp. 591–599, 2010. View at: Publisher Site | Google Scholar
  44. K. Schindler, D. Haider, M. Wolzt et al., “Impact of antiretroviral therapy on visfatin and retinol-binding protein 4 in HIV-infected subjects,” European Journal of Clinical Investigation, vol. 36, no. 9, pp. 640–646, 2006. View at: Publisher Site | Google Scholar
  45. J. M. Leitner, H. Pernerstorfer-Schoen, A. Weiss, K. Schindler, A. Rieger, and B. Jilma, “Age and sex modulate metabolic and cardiovascular risk markers of patients after 1 year of highly active antiretroviral therapy (HAART),” Atherosclerosis, vol. 187, no. 1, pp. 177–185, 2006. View at: Publisher Site | Google Scholar
  46. C. C. Smith and D. M. Yellon, “Adipocytokines, cardiovascular pathophysiology and myocardial protection,” Pharmacology and Therapeutics, vol. 129, pp. 206–219, 2011. View at: Publisher Site | Google Scholar
  47. K. Falasca, C. Ucciferri, P. Mancino et al., “Cystatin C, adipokines and cardiovascular risk in HIV infected patients,” Current HIV Research, vol. 8, no. 5, pp. 405–410, 2010. View at: Publisher Site | Google Scholar
  48. H. Mangge, G. Almer, M. Truschnig-Wilders, A. Schmidt, R. Gasser, and D. Fuchs, “Inflammation, adiponectin, obesity and cardiovascular risk,” Current Medicinal Chemistry, vol. 17, no. 36, pp. 4511–4520, 2010. View at: Google Scholar
  49. J. Cui, S. Panse, and B. Falkner, “The role of adiponectin in metabolic and vascular disease: a review,” Clinical Nephrology, vol. 75, no. 1, pp. 26–33, 2011. View at: Publisher Site | Google Scholar
  50. S. Das, M. Shahmanesh, M. Stolinski et al., “In treatment-naïve and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100,” Diabetologia, vol. 49, no. 3, pp. 538–542, 2006. View at: Publisher Site | Google Scholar
  51. J. L. Sankale, Q. Tong, C. M. Hadigan et al., “Regulation of adiponectin in adipocytes upon exposure to HIV-1,” HIV Medicine, vol. 7, no. 4, pp. 268–274, 2006. View at: Publisher Site | Google Scholar
  52. Q. Tong, J. L. Sankale, C. M. Hadigan et al., “Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1559–1564, 2003. View at: Publisher Site | Google Scholar
  53. L. Luo, L. Zhang, M. Tao et al., “Adiponectin and leptin levels in Chinese patients with hiv-related lipodystrophy: a 30-month prospective study,” AIDS Research and Human Retroviruses, vol. 25, no. 12, pp. 1265–1272, 2009. View at: Publisher Site | Google Scholar
  54. G. P. Bezante, L. Briatore, D. Rollando et al., “Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 19, no. 4, pp. 277–282, 2009. View at: Publisher Site | Google Scholar
  55. R. Nogueiras, M. G. Novelle, M. J. Vazquez, M. Lopez, and C. Dieguez, “Resistin: regulation of food intake, glucose homeostasis and lipid metabolism,” Endocrine Development, vol. 17, pp. 175–184, 2010. View at: Publisher Site | Google Scholar
  56. K. Ranade, W. J. Geese, M. Noor et al., “Genetic analysis implicates resistin in HIV lipodystrophy,” AIDS, vol. 22, no. 13, pp. 1561–1568, 2008. View at: Publisher Site | Google Scholar
  57. X. Escote, M. Miranda, S. Veloso et al., “Lipodystrophy and insulin resistance in combination antiretroviral treated HIV-1-infected patients: implication of resistin,” Journal of Acquired Immune Deficiency Syndromes, vol. 57, no. 1, pp. 16–23, 2011. View at: Publisher Site | Google Scholar
  58. M. S. Jamaluddin, S. M. Weakley, Q. Yao, and C. Chen, “Resistin: functional roles and therapeutic considerations for cardiovascular disease,” British Journal of Pharmacology. In press. View at: Publisher Site | Google Scholar
  59. Y. Cho, S. E. Lee, H. C. Lee et al., “Adipokine resistin is a key player to modulate monocytes, endothelial cells, and smooth muscle cells, leading to progression of atherosclerosis in rabbit carotid artery,” Journal of the American College of Cardiology, vol. 57, no. 1, pp. 99–109, 2011. View at: Publisher Site | Google Scholar
  60. B. Samal, Y. Sun, G. Stearns, C. Xie, S. Suggs, and I. McNiece, “Cloning and characterization of the cDNA encoding a novel human pre-B- cell colony-enhancing factor,” Molecular and Cellular Biology, vol. 14, no. 2, pp. 1431–1437, 1994. View at: Google Scholar
  61. Y. H. Chang, D. M. Chang, K. C. Lin, S. J. Shin, and Y. J. Lee, “Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review,” Diabetes/Metabolism Research and Reviews, vol. 27, no. 6, pp. 515–527, 2011. View at: Publisher Site | Google Scholar
  62. A. Esteghamati, A. Alamdari, A. Zandieh et al., “Serum visfatin is associated with type 2 diabetes mellitus independent of insulin resistance and obesity,” Diabetes Research and Clinical Practice, vol. 91, no. 2, pp. 154–158, 2011. View at: Publisher Site | Google Scholar
  63. K. Schindler, D. Haider, M. Wolzt et al., “Impact of antiretroviral therapy on visfatin and retinol-binding protein 4 in HIV-infected subjects,” European Journal of Clinical Investigation, vol. 36, no. 9, pp. 640–646, 2006. View at: Publisher Site | Google Scholar
  64. N. P. Kadoglou, A. Gkontopoulos, A. Kapelouzou et al., “Serum levels of vaspin and visfatin in patients with coronary artery disease-Kozani study,” Clinica Chimica Acta, vol. 412, no. 1-2, pp. 48–52, 2011. View at: Publisher Site | Google Scholar
  65. N. P. Kadoglou, N. Sailer, A. Moumtzouoglou et al., “Visfatin (Nampt) and ghrelin as novel markers of carotid atherosclerosis in patients with type 2 diabetes,” Experimental and Clinical Endocrinology and Diabetes, vol. 118, no. 2, pp. 75–80, 2010. View at: Publisher Site | Google Scholar
  66. T. B. Dahl, A. Yndestad, M. Skjelland et al., “Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization,” Circulation, vol. 115, no. 8, pp. 972–980, 2007. View at: Publisher Site | Google Scholar
  67. F. Soriguer, L. Garrido-Sanchez, S. Garcia-Serrano et al., “Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus,” Obesity Surgery, vol. 19, no. 11, pp. 1574–1580, 2009. View at: Publisher Site | Google Scholar
  68. M. J. Kleinz, J. N. Skepper, and A. P. Davenport, “Immunocytochemical localisation of the apelin receptor, APJ, to human cardiomyocytes, vascular smooth muscle and endothelial cells,” Regulatory Peptides, vol. 126, no. 3, pp. 233–240, 2005. View at: Publisher Site | Google Scholar
  69. C. Carpene, C. Dray, C. Attane et al., “Expanding role for the apelin/APJ system in physiopathology,” Journal of Physiology and Biochemistry, vol. 63, no. 4, pp. 359–374, 2007. View at: Google Scholar
  70. N. P. Kadoglou, S. Lampropoulos, A. Kapelouzou et al., “Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease-KOZANI STUDY,” Translational Research, vol. 155, no. 5, pp. 238–246, 2010. View at: Publisher Site | Google Scholar
  71. A. M. Kuklinska, B. Sobkowicz, R. Sawicki et al., “Apelin: a novel marker for the patients with first ST-elevation myocardial infarction,” Heart and Vessels, vol. 25, no. 5, pp. 363–367, 2010. View at: Publisher Site | Google Scholar
  72. M. X. Zou, H. Y. Liu, Y. Haraguchi, Y. Soda, K. Tatemoto, and H. Hoshino, “Apelin peptides block the entry of human immunodeficiency virus (HIV),” FEBS Letters, vol. 473, no. 1, pp. 15–18, 2000. View at: Publisher Site | Google Scholar
  73. B. A. Puffer, M. Sharron, C. M. Coughlan et al., “Expression and coreceptor function of APJ for primate immunodeficiency viruses,” Virology, vol. 276, no. 2, pp. 435–444, 2000. View at: Publisher Site | Google Scholar
  74. J. Wada, “Vaspin: a novel serpin with insulin-sensitizing effects,” Expert Opinion on Investigational Drugs, vol. 17, no. 3, pp. 327–333, 2008. View at: Publisher Site | Google Scholar
  75. Q. Li, R. Chen, J. Moriya et al., “A novel adipocytokine, visceral adipose tissue-derived serine protease inhibitor (vaspin), and obesity,” Journal of International Medical Research, vol. 36, no. 4, pp. 625–629, 2008. View at: Google Scholar
  76. G. Aust, O. Richter, S. Rohm et al., “Vaspin serum concentrations in patients with carotid stenosis,” Atherosclerosis, vol. 204, no. 1, pp. 262–266, 2009. View at: Publisher Site | Google Scholar
  77. S. Tsiodras, A. Perelas, C. Wanke, and C. S. Mantzoros, “The HIV-1/HAART associated metabolic syndrome—novel adipokines, molecular associations and therapeutic implications,” Journal of Infection, vol. 61, no. 2, pp. 101–113, 2010. View at: Publisher Site | Google Scholar

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