leptin and HIV-Associated-Lipodystrophy-Syndrome

Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy.

Topics: Animals; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Lipodystrophy; Metabolic Diseases

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Topics: Animals; Diabetes Mellitus; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Receptors, Leptin; Signal Transduction

The use of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus has dramatically altered both the landscape of this disease and the prognosis for those affected. With more patients now receiving HAART, adverse effects such as lipodystrophy and metabolic syndrome have emerged. In HIV/HAART-associated lipodystrophy syndrome (HALS), patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Recent studies have contributed to the elucidation of the pathophysiological abnormalities seen in this syndrome and have provided guidance for the study and use of potential treatments for these patients, but widely accepted guidelines have not yet been established. Two adipokines, leptin and adiponectin, are decreased in patients with HALS and lipoatrophy or lipodystrophy. Further, recent proof-of-concept clinical trials have proven the efficacy of leptin replacement and medications that increase circulating adiponectin levels in improving the metabolic profile of HALS patients. This review article highlights recent evidence on leptin replacement and compares leptin's efficacy to that of other treatments, including metformin and thiazolidinediones, on metabolic abnormalities such as impaired insulin-glucose homeostasis associated with lipodystrophy in patients receiving HAART. It is hoped that forthcoming large phase III clinical trials will allow the addition of leptin to our therapeutic armamentarium for use in patients suffering from this disease state.

Topics: Adiponectin; Glucose Intolerance; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Metformin; Thiazolidinediones

Topics: Adiponectin; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Neurosecretory Systems; Peptide Hormones; Resistin

Lipodystrophy (LD) with varying degrees of lipohypertrophy, lipoatrophy, hyperlipidemia, and insulin resistance is one of the complications of highly active antiretroviral therapy (HAART) and occurs in one to 33 % of HAART-treated, HIV infected children. We summarize the data on the role of leptin, adiponectin, the growth hormone axis, glucocorticoids, sterol response element binding protein 1c (SREBP-1c), the tumor necrosis factor alpha axis (TNF-alpha), interleukin-6 (IL-6), interleukin- 18 (IL-18), interferon-alpha (IFN-alpha), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1) in the pathophysiology of LD. Adiponectin levels are generally decreased in LD, whereas leptin levels are increased. Systemic cortisol levels are not elevated in LD, even though glucocorticoids seem to play an important role in LD and the phenotype can be reminiscent of Cushing syndrome. GH resistance in LD needs to be better characterized. While some cytokines show promise as markers for LD, it is difficult to tell whether their derangement is a cause of or the effect of LD.

Topics: Adiponectin; Adolescent; Antiretroviral Therapy, Highly Active; Child; Cytokines; Fibrinolysis; Glucocorticoids; HIV-Associated Lipodystrophy Syndrome; Human Growth Hormone; Humans; Leptin; Sterol Regulatory Element Binding Protein 1

Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02 mg/kg/d for two months; 0.04 mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of (13)C(1)-palmitate and (2)H(5)-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose-dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P<.01) and area-under-the-curve for glucose (P<.05). In hypoleptinemic HADL patients, treatment with metreleptin at 0.02 or 0.04 mg/kg/d does not improve abnormal fasting lipid kinetics, or triglyceride or HDL-C levels. Metreleptin does, however, improve glycemia and non-HDL-C in these patients. These results suggest a dissociation between leptin's effects on glucose metabolism compared to those on lipid kinetics in HADL.

Topics: Adult; Blood Glucose; Double-Blind Method; Fatty Acids, Nonesterified; HIV-Associated Lipodystrophy Syndrome; Hormone Replacement Therapy; Humans; Leptin; Lipids; Middle Aged

Highly active antiretroviral therapy (HAART)-induced lipoatrophy is characterized by hypoleptinemia and insulin resistance. Evidence suggests that pioglitazone and recombinant methionyl human leptin (metreleptin) administration has beneficial effects in human immunodeficiency virus (HIV)-infected lipoatrophic patients. This proof-of-concept study aimed at evaluating whether the combination of metreleptin and pioglitazone has favorable effects, above and beyond pioglitazone alone, on both metabolic outcomes and peripheral lipoatrophy in HIV-infected patients on HAART. Nine HIV-positive men with at least 6 months of HAART exposure, clinical evidence of lipoatrophy, and low leptin concentrations (≤4 ng/mL) were placed on pioglitazone treatment (30 mg/d per os) and were randomized to receive either metreleptin (0.04 mg/kg subcutaneously once daily; n = 5) or placebo (n = 4) for 3 months in a double-blinded fashion. Compared with placebo, metreleptin reduced fasting serum insulin concentration, increased adiponectin concentration, reduced the homeostasis model assessment index of insulin resistance, and attenuated postprandial glycemia in response to a mixed meal (all P ≤ .02), but did not affect trunk and peripheral fat mass. HIV control was not affected, and no major adverse effects were observed. Metreleptin administration in HIV-positive, leptin-deficient patients with lipoatrophy treated with pioglitazone improves postprandial glycemia and insulin sensitivity. Results from this pilot study should be confirmed in larger clinical trials.

Topics: Adiponectin; Adult; Antiretroviral Therapy, Highly Active; Blood Glucose; Body Mass Index; Drug Therapy, Combination; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Pilot Projects; Pioglitazone; Postprandial Period; Thiazolidinediones

Metabolic syndrome (MetS) is more common in HIV-infected adults and children than in the general population. Adipocytokines and inflammatory markers may contribute to the pathophysiology of this condition and could be useful indices for monitoring MetS. The objective of this study was to provide information on the prevalence of MetS and investigate the role of adipocytokines and other biomarkers in this syndrome in HIV-infected pediatric patients.. A cross-sectional study was conducted between October 2013 and March 2014 in the outpatient clinics of 2 tertiary pediatric referral hospitals. Fifty-four HIV-infected children and adolescents were included. MetS was defined according to the International Diabetes Federation and modified National Cholesterol Education Program Adult Treatment Panel III criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin, adiponectin, leptin, interleukin-6, vitamin D and C-reactive protein and clinical lipodystrophy assessment.. Among the total, 3.7% of patients met the International Diabetes Federation criteria for MetS and 7.4% met the National Cholesterol Education Program Adult Treatment Panel III criteria. C-reactive protein and leptin levels were significantly higher and adiponectin level significantly lower in patients with MetS, regardless of the criteria used. Insulin resistance was observed in 40.7% of patients; abnormal quantitative insulin sensitivity check index values were found in 88.9%. Eighteen patients (33.3%) had vitamin D deficiency.. The prevalence of MetS was similar to that observed in larger cohorts of HIV-infected patients in our setting. Adipocytokine dysregulation seems to be related to MetS in HIV-infected children. A high percentage of patients showed insulin resistance, which should be strictly monitored.

Topics: Adiponectin; Adolescent; Biomarkers; Child; Cross-Sectional Studies; Female; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Risk Factors; Spain; Vitamin D Deficiency

Impaired production of adipocytokines is a major factor incriminated in the occurrence of lipodystrophy (LD).. To evaluate LD prevalence and subtypes in HIV treatment-multiexperienced patients, and to determine the correlations between adipocytokines and LD subtypes.. Cross-sectional study in a Romanian tertiary care hospital, between 2008 and 2010, in HIV-positive patients, undergoing cART for ≥6 months. LD diagnosis, based on clinical and anthropometric data, was classified into lipoatrophy (LA), lipohypertrophy (LH) and mixed fat redistribution (MFR). Blood samples were collected for leptin, adiponectin and resistin assessments.. We included 100 patients, 44 % with LD, among which LA had 63 %. LA patients had sex ratio, median age, treatment duration and median number of ARV regimens of 1, 20, 93 and 3.5 compared to non-LD patients: 1.65, 31, 44 and 1. LH and MFR patients were older and had higher total and LDL cholesterol versus non-LD patients. For both overall group and female group, LA was associated in univariate and multivariate analysis with increased resistin (p = 0.02 and 0.04) and number of ARV regimens (p < 0.001). Determination coefficient (Nagelkerke R (2)) of increased resistin and the number of ARV combinations in the presence of LA was 33 % in overall group and 47 % in female patients.. In our young HIV-positive population, LD had high prevalence with predominance of LA subtype. LA was associated with high resistin levels and greater number of ARV regimens in overall group and female subgroup. Resistin could be used as a marker of peripheral adipose tissue loss and might be used as a target for new anti-LD therapeutic strategies.

Topics: Adiponectin; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cross-Sectional Studies; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Male; Middle Aged; Prevalence; Resistin; Young Adult

Topics: HIV-Associated Lipodystrophy Syndrome; Hormone Replacement Therapy; Humans; Leptin; Lipids

The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients.. A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR).. The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031).. cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue.

Topics: Adiponectin; Adult; Anti-Retroviral Agents; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Drug Therapy, Combination; Fatty Acid-Binding Proteins; Female; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Interleukin-18; Leptin; Male; Metabolic Diseases; Middle Aged; Tumor Necrosis Factor-alpha

Highly active antiretroviral therapy might lead to the development of dyslipidemia and lipodystrophy (LD) syndrome. We carried out a multicenter prospective study of 22 human immunodeficiency virus (HIV)-1-infected children treated during 48 months with lopinavir/ritonavir-based highly active antiretroviral therapy to evaluate the trend of serum lipids and adipokines. Increase in plasma leptin levels and leptin/adiponectin ratio was associated with LD. These adipokines may be surrogate markers of LD.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; Child; Child, Preschool; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Leptin; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Lipoatrophy and metabolic complications of treatment of human immunodeficiency virus (HIV) infection may share common associations with adipose tissue pathology and inflammation. To investigate these relationships, we undertook a large-scale study of adipose tissue, body composition, and metabolic outcomes among HIV-infected adult men at a tertiary hospital HIV cohort during the period 2001-2007.. Assessments included adipose biopsies (n = 211) for investigation of adipocyte mitochondrial DNA content, adipocytokine expression, and adipose macrophage content; and whole-body dual-energy x-ray absorptiometry (DEXA) scans (n = 225) for objective body composition changes; 138 individuals contributed both biopsy and DEXA data.. Compared with 78 treatment-naive control subjects, 98 zidovudine recipients (48%) and 49 stavudine recipients (67%) had leg fat measures <10% threshold value. Adipose samples associated with current stavudine or zidovudine (n = 99) revealed significant adipocyte mitochondrial DNA depletion, adipose tissue macrophage infiltration, and elevated proinflammatory cytokine levels, compared with samples from control subjects and nonthymidine nucleoside reverse-transcriptase inhibitor (NRTI) recipients (all P < .05). Improvements in adipose pathology after NRTI switching (n = 21 longitudinal samples) correlated with increased preswitch adipose inflammation and less severe fat loss (both P < .05). Elevated ratios of total to high-density lipoprotein cholesterol levels and Homeostatic Metabolic Assessment scores correlated independently with lipoatrophy severity (P < .05) and increased body mass index (P < .05) in thymidine NRTI-experienced individuals. No effect of demographic or HIV-related variables, or HIV protease inhibitor therapy exposure was detected.. Adipose tissue pathology and lipoatrophic fat loss are highly prevalent among recipients of stavudine- or zidovudine-based HIV treatment and are associated with adverse metabolic outcomes. Restoring adipose tissue health appears to be an important issue in the long-term treatment of this patient population.

Topics: Adiponectin; Adipose Tissue; Adult; Anti-HIV Agents; Body Composition; Case-Control Studies; DNA, Mitochondrial; Gene Expression Regulation; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Interleukin-8; Leptin; Macrophages; Male; Middle Aged; Prevalence

This study aimed to investigate the association between 4 polymorphisms in the leptin, leptin receptor, and adiponectin (APM1) genes and the occurrence of lipodystrophy and dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy (HAART).. Genotypes of 410 HIV-infected patients on HAART were investigated. Anthropometric (weight, height, waist circumference and skinfolds thickness) and biochemical (blood lipids, glucose, leptin, and adiponectin levels) parameters were evaluated. Genotype frequencies were compared between patients with or without lipodystrophy. Mean biochemical and anthropometric parameters were compared between the different genotypes.. Lipodystrophy prevalence was 53.4%. Genotype frequencies were not different between patients with or without lipodystrophy. Carriers of the A allele for the APM1-11391 G.A and of the C allele for APM1-11377 C.G presented higher adiponectin levels compared to other genotypes, and carriers of the -11391A-11377C haplotype when compared with carriers of other haplotypes.. SNPs in APM1 gene are associated with adiponectin levels in HIV-infected patients receiving HAART and may thus affect the occurrence of metabolic alterations in these patients. No influence of the leptin and leptin receptor gene polymorphisms on the occurrence of lipodystrophy and dyslipidemia was observed.

Topics: Adiponectin; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Leptin

Lipodystrophy in HIV type-1 (HIV-1)-infected patients is the consequence of effects originating from antiretroviral treatment and HIV-1 infection. We have studied adipose tissues and circulating parameters in mice bearing the HIV-1 transgene as a model to provide insight into the role of HIV-1-infection-related events in fat alterations.. Heterozygous transgenic mice expressing a 7.7 kb HIV-1 construct (Tg26+/-) were used. Cytokine and adipokine levels were quantified using multiplex procedures. Gene expression and mitochondrial DNA abundance in visceral and subcutaneous white adipose tissues and in brown fat were determined using quantitative real-time PCR.. The amount of visceral, but not subcutaneous, adipose depot was lower in Tg26+/- mice. Serum proinflammatory cytokine levels were increased in Tg26+/- mice, whereas adiponectin and leptin levels were reduced. Gene expression of monocyte chemoattractant protein-1 was induced in visceral and subcutaneous fat, whereas tumour necrosis factor-α and interleukin-6 were induced in visceral and subcutaneous white adipose tissues, respectively. Adiponectin and leptin gene expression was repressed in all white fat depots, in concert with reduced expression of peroxisome proliferator-activated receptor γ, a master controller of adipogenesis. In brown fat, a coordinate induction in the expression of thermogenesis marker genes was observed.. HIV-1 transgene expression in mice causes changes in adipose tissue reminiscent of those in patients with HIV-1 lipodystrophy, particularly early pretreatment changes. These data support a role for HIV-1-infection-related events in eliciting adipose tissue dysfunction. The Tg26+/- mouse appears as a promising model to assess the effects of HIV-1 infection on adipose tissue and for determining the effects of antiretroviral drugs on an HIV-1-infected background.

Topics: Adipogenesis; Adipokines; Adiponectin; Adipose Tissue; Animals; Antiretroviral Therapy, Highly Active; Chemokine CCL2; Disease Models, Animal; Gene Expression Profiling; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Interleukin-6; Leptin; Male; Mice; Mice, Transgenic; Subcutaneous Fat; Subcutaneous Tissue

The relationship of adipocytokine with the development of HIV-related lipodystrophy was investigated in a case-control study. Adipocytokine, lipid, and glycemic parameters were measured at every visit. Logistic regression analysis was used to assess the HIV-LD risk factors and the Spearman correlation coefficients test was used to assess the correlation between adiponectin with other metabolic variables. Most of the patients (96.3%) developed HIV-LD after month 12. Comparing the baseline adiponectin, the adiponectin concentration of the HIV-LD group rose by month 6 and began to decrease substantially by month 18; this reduction was maintained until month 30 (p < 0.05). Comparing the HIV-NLD group, the adiponectin concentration at months 18, 24, and 30 were significantly lower in the HIV-LD group. The leptin concentration of both the HIV-LD and HIV-NLD groups remained stable. Patients in the lower concentration of baseline adiponectin and greater adiponectin change rate at month 18 presented with increased odds ratio for HIV-LD. The adiponectin level had a correlation with serum triglycerides (r = -0.616, p < 0.0001), serum insulin concentration (r = -0.494, p = 0.001), and HDL-C (r = 0.673, p < 0.0001). The adiponectin concentration of HIV-LD began to decrease substantially by month 18. The lower baseline concentration of adiponectin and the greater change rate at month 18 were independent risk factors of HIV-LD. The adiponectin level had a correlation with serum triglycerides, serum insulin concentration, and HDL-C, suggesting that adiponectin may link the metabolic abnormalities and HIV-LD.

Topics: Adiponectin; Adult; Antiretroviral Therapy, Highly Active; Asian People; Case-Control Studies; Female; Follow-Up Studies; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Leptin; Logistic Models; Male; Prospective Studies; Risk Factors; Triglycerides

Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV(+) in children. Human immunodeficiency-associated lipodystrophy syndrome (HALS) is a side effect of HAART seen predominantly in adults and less often in children. Leptin is a protein thought to play an important role in body composition and has been shown to have immunomodulatory effects. We retrospectively studied serum levels of leptin in a cohort of eight HIV-infected children followed prospectively before and during HAART and investigated whether there is a correlation of these levels with the clinical, immunological, viral or nutritional changes observed during treatment in these children. None of our children developed HALS. In this small cohort of children, we found that serum leptin levels were appropriate to the nutritional status of the patient and that leptin/BMI increased in patients who responded to HAART. In conclusion, in HIV(+) children during HAART, leptin levels are related to the nutritional status of the child.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Mass Index; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Cohort Studies; Female; HIV; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Leptin; Male; Nutritional Status; Retrospective Studies; Statistics, Nonparametric; Viral Load

HIV-related lipodystrophy is a syndrome of adipose tissue redistribution, dyslipidaemia and insulin resistance. Combination antiretroviral therapy (CART) is a key risk factor. We hypothesized that fat redistribution in HIV-infected children is related to altered endocrine function of adipose tissue, namely leptin secretion.. Serum leptin and fat redistribution were measured in 104 HIV-infected children in a prospective observational study from 2003 to 2004. Fat redistribution was defined by clinical observation. Body fatness was estimated using body mass index and four skinfold measurements. Serum leptin was determined using an enzyme-linked immunosorbent assay (Quantikine; R&D Systems, Abingdon, UK). Linear analogue models were used to adjust the leptin concentration for body fatness.. There was no significant difference in serum leptin among children treated with protease inhibitors (PIs), children on non-PI CART and children not treated with CART (P>0.05). When leptin concentrations were adjusted for body fatness, there was again no difference among PI-treated, non-PI-treated and untreated children. Categorization of CART exposure as never, current or past did not change these results.. There is no evidence that leptin plays any role in lipodystrophy other than reflecting body fatness.

Topics: Adipose Tissue; Adolescent; Analysis of Variance; Antiretroviral Therapy, Highly Active; Child; Female; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Male; Prospective Studies; Risk Factors

Highly active antiretroviral therapy (HAART) for HIV-1 infection has been associated with a metabolic syndrome characterized by insulin resistance, hyperlipidemia, and redistribution of body fat (lipodystrophy). A subset of patients with predominant lipoatrophy has low levels of the adipocyte-secreted hormone leptin.. The objective of the study was to assess whether administration of recombinant methionyl human leptin (r-metHuLeptin) improves insulin resistance and other metabolic abnormalities in HIV+ leptin-deficient subjects with HAART-induced lipoatrophy.. We conducted a randomized, placebo-controlled, double-blinded, crossover study from 2002 to 2004 in seven HIV+ men with HAART-induced lipoatrophy, serum leptin level less than 3 ng/ml, and fasting triglyceride level greater than 300 mg/dl, who were administered placebo for 2 months before or after administration of r-metHuLeptin at physiological doses for an additional 2 months.. Insulin resistance, lipid levels, inflammatory markers, body composition, and HIV control were measured.. Compared with placebo, r-metHuLeptin therapy improved fasting insulin levels, insulin resistance (as expressed by the homeostasis model assessment index and an insulin suppression test), and high-density lipoprotein. Body weight and fat mass decreased on r-metHuLeptin, mainly due to a decrease in truncal fat but not peripheral fat or lean body mass. r-metHuLeptin was well tolerated, and HIV control was not adversely affected.. r-metHuLeptin replacement at physiological doses in HIV+ leptin-deficient patients with HAART-induced lipoatrophy improves insulin resistance, high-density lipoprotein, and truncal fat mass. Future larger and more long-term studies in HAART-induced lipoatrophy, including patients with more severe metabolic abnormalities, are warranted to evaluate the physiological and potentially therapeutic role of r-metHuLeptin for this condition and to fully clarify the underlying mechanisms of action.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Antiretroviral Therapy, Highly Active; Body Composition; Body Mass Index; Cross-Over Studies; Double-Blind Method; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Lipids; Lipoproteins, HDL; Male; Metabolic Syndrome; Placebos; Recombinant Proteins

Human immunodeficiency virus (HIV)-related lipodystrophy is characterized by adipose tissue redistribution, dyslipidemia, and insulin resistance. We hypothesized that fat redistribution and metabolic abnormalities in HIV-infected children are related to alterations in endocrine function of adipose tissue. A multicenter study was conducted in 130 HIV-infected children. Lipodystrophy definition was based on the central to peripheral skinfold ratio. Fasting adiponectin, leptin, insulin concentrations, glycemia, and lipid profile were measured in all children. Fat redistribution syndrome was apparent in 32 children: 14 with atrophic (LPDA) and 18 with hypertrophic lipodystrophy (LPDH). Mean serum adiponectin levels were significantly decreased in LPDA and LPDH groups compared with the group with no lipodystrophy (LPD-). Fasting insulin concentration was significantly higher in LPDA and LPDH groups versus LPD-. Mean serum leptin concentration was significantly increased only in LPDH compared with LPDA and LPD- groups. Triglyceride levels were significantly increased and high-density lipoprotein (HDL)-cholesterol concentration decreased in the LPDA versus LPD- group. Controlling for puberty stage, gender, percentage of total fat mass, serum lipids, HIV treatment, and disease severity, adiponectin was significantly and inversely associated with central obesity and insulin/glucose ratio. Fat redistribution had no significant effect on leptin concentration, which was directly related to the percentage of body fat, female gender, and insulin/glucose ratio. In conclusion, HIV-infected children with symptoms of fat redistribution have decreased levels of adiponectin, associated with insulin resistance and dyslipidemia.

Topics: Acquired Immunodeficiency Syndrome; Adiponectin; Adolescent; Blood Glucose; Child; Child, Preschool; Dyslipidemias; Early Diagnosis; Female; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male

The lipodystrophic syndrome (LD) is a disorder resulting from selective damage of adipose tissue by antiretroviral drugs included in therapy controlling human-immunodeficiency-virus-1. In the therapy cocktail the nucleoside reverse transcriptase inhibitors (NRTI) contribute to the development of this syndrome. Cellular target of NRTI was identified as the mitochondrial polymerase-gamma and their toxicity described as a mitochondrial DNA (mtDNA) depletion resulting in a mitochondrial cytopathy and involved in fat redistribution. No mechanisms offer explanation whatsoever for the lipo-atrophic and lipo-hypertrophic phenotype of LD. To understand the occurrence we proposed that the pO2 (oxygen partial pressure) could be a key factor in the development of the LD. For the first time, we report here differential effects of NRTIs on human adipose cells depending on pO2 conditions.. We showed that the hypoxia conditions could alter adipogenesis process by modifying expression of adipocyte makers as leptin and the peroxisome proliferator-activated receptor PPARgamma and inhibiting triglyceride (TG) accumulation in adipocytes. Toxicity of NRTI followed on adipose cells in culture under normoxia versus hypoxia conditions showed, differential effects of drugs on mtDNA of these cells depending on pO2 conditions. Moreover, NRTI-treated adipocytes were refractory to the inhibition of adipogenesis under hypoxia. Finally, our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat.. Toxicity of NRTIs have been shown to be opposite on human adipose cells depending on the oxygen availability. These data suggest that the LD phenotype may be a differential consequence of NRTI effects, depending on the metabolic status of the targeted adipose tissues and provide new insights into the opposite effects of antiretroviral treatment, as observed for the lipo-atrophic and lipo-hypertrophic phenotype characteristic of LD.

Topics: Adipogenesis; Adipose Tissue; Cells, Cultured; DNA, Mitochondrial; Gene Expression Regulation; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoxia; Leptin; Oligopeptides; Oxygen; Peptides, Cyclic; Phenotype; PPAR gamma; Reverse Transcriptase Inhibitors; Somatostatin; Triglycerides

Significant advances in the treatment of the morbidity and mortality associated with AIDS are also associated with undesirable side-effects in fat redistribution (lipodystrophy), insulin resistance and cardiovascular risk, which is directly linked to protease inhibitor (PI) treatment.. The effects of four different PIs on triglyceride (TG) storage and adipokine production (leptin, adiponectin, and acylation stimulating protein [ASP]) in omental (OM) and subcutaneous (SC) adipose tissues were examined.. Initial results demonstrated that saquinivir (SQV) and ritonivir (RTV) had little observed effect on de novo TG synthesis ([3H]glucose incorporation into TG) or fatty acid re-esterification ([14C]oleate incorporation into TG), whereas amprenivir (APV) and indinivir (IDV) reduced TG synthesis, especially in SC tissue up to 30+/-5.8% P<0.05 and 46+/-7.8% P<0.001, at 20 microM, respectively. There was no observed effect on phospholipid synthesis, tissue protein or toxicity. Only APV and IDV decreased leptin and adiponectin secretion in SC tissue, in a time- and concentration-dependent manner: at 18 h, leptin was inhibited by 54+/-3.1% (P<0.001) and 44+/-6.4% (P<0.001) by APV and IDV (40 microM), respectively, and adiponectin was inhibited by 35+/-5.6%(P<0.001) and 25+/-12.3% (P<0.05) by APV and IDV (40 IuM), respectively. By contrast, both IDV and APV decreased ASP secretion in OM tissues by a maximum of 53 +/-7.8% (P<0.001) and 59+/-5.9% (P<0.001), respectively, and by a maximum of 86+/-1.6% (P<0.001) and 72 +/-4% (P<0.001), respectively, in SC tissues.. PI have a direct effect on human adipose tissue which are site, PI and adipokine specific; these effects may contribute to the overall adipose imbalance and development of lipodystrophy, and metabolic syndrome in HIV-positive individuals.

Topics: Adiponectin; Adipose Tissue; Adult; Female; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Lipid Metabolism; Male; Middle Aged; Omentum; Subcutaneous Fat; Triglycerides

To assess the correlations between the hormone leptin and lipoatrophy in HIV-positive, treatment-naive patients on combination antiretroviral therapy (cART).. Case-control study nested in a multicentre cohort of HIV-infected adults. Cases were patients that developed lipoatrophy and controls those who did not.. Clinical parameters and plasma leptin determinations were studied in 97 HIV-1-infected, treatment-naive Caucasian men (10 cases and 87 controls) on an unchanged and virologically successful drug regimen with a zidovudine/lamivudine backbone at baseline and after 2 years of cART. The association of plasma leptin levels and the development of lipoatrophy was investigated.. Two years of cART was not associated with a change in plasma leptin levels. Plasma leptin levels remained sensible to changes in body mass index. There was no difference in leptin levels between patients who developed lipoatrophy and controls, neither before nor after cART. The only predictor of development of lipoatrophy was a higher age (P = 0.02).. Leptin as measured in plasma is unlikely to play a major role in the genesis of lipoatrophy.

Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Body Mass Index; Case-Control Studies; Cohort Studies; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Leptin; Male; Middle Aged; Viral Load

To achieve a better understand of the pathophysiology of HIV-related lipoatrophy, we compared the mRNA expression of adipocytokines in fat samples from patients and healthy HIV-seronegative controls together with fat morphology and we studied the relationship between changes in fat morphology, adipocytokine expression, markers of adipose tissue differentiation and whole body insulin sensitivity.. Cross-sectional analytical study.. The mRNA expression of adipocytokines and transcriptional factors in fat samples from 26 patients with peripheral lipoatrophy (all under anti-retroviral therapy associating protease inhibitor and nucleoside-analogue reverse transcriptase inhibitors) and from 16 non-HIV-infected controls was measured by real time quantitative RT-PCR. Fat morphology was assessed histologically on a subgroup of 10 patients and six controls: collagen fibres by Sirius Red staining, apoptosis by the TUNEL technique, vessels by smooth muscle alpha-actin staining and macrophages by CD68 staining. Insulin resistance was assessed by using the homeostasis model assessment.. The patients' fat showed higher values of apoptosis (P=0.005), fibrosis (P<0.05), vessel density (P=0.001) and macrophage infiltration (P<0.05) than the controls' fat, together with lower adiponectin and leptin mRNA levels and higher interleukin (IL)-6 and tumour necrosis factor (TNF)alpha mRNA levels. TNFa and IL-6 expression correlated positively with the level of apoptosis (P=0.05 and P<0.05, respectively) and negatively with CCAAT-enhancer binding protein (C/EBP)alpha (P<0.001 and P<0.05, respectively). Apoptosis correlated negatively with the expression level of sterol-regulatory-element-binding-protein-1c (SREBP1c) (P=0.01) and C/EBPalpha (P=0.01) whilst the vessel density correlated negatively with SREBP1c (P<0.005), C/EBPalpha (P=0.001) and beta (P=0.001). Adiponectin and leptin expression correlated positively with each other, and also with adipogenic marker expression and overall insulin sensitivity. These relationships were also present when the patient group was studied separately. Finally, fat morphological abnormalities correlated positively with whole body insulin resistance.. Adipose tissue from patients with HIV-1-related lipoatrophy shows increased apoptosis, together with decreased adipocyte differentiation. Increased TNFalpha and IL-6 expression could be a major phenomenon linking these alterations. Decreased adiponectin and leptin expression, which may result from decreased adipocyte differentiation, could be involved in the observed whole body insulin resistance.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adult; Apoptosis; Blood Vessels; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; Cross-Sectional Studies; DNA-Binding Proteins; Female; Fibrosis; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Macrophages; Male; Middle Aged; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Tumor Necrosis Factor-alpha

A lipodystrophic syndrome and metabolic abnormalities have been observed in HIV-infected patients treated with highly active antiretroviral therapy (HAART). A murine model of lipodystrophy is associated with decreased levels of adiponectin, an adipocyte-secreted protein, the administration of which improves the metabolic syndrome in these mice. To investigate the association of adiponectin with metabolic changes in human lipodystrophy, we conducted a cross-sectional study of 112 HIV-infected patients treated with HAART. Mean adiponectin levels were higher in patients with no fat redistribution (FR) vs. FR (4.8 +/- 5.0 vs. 2.2 +/- 2.7 microg/ml, P < 0.01), but no significant differences in adiponectin levels were observed between FR subgroups. The difference in adiponectin levels between subjects with and without FR remained significant after adjusting for age, gender, leptin, HIV medication use, and CD4 count using logistic regression (odds ratio, 0.54, P = 0.008). Adiponectin was significantly correlated with triglycerides (r = -0.40), abdominal visceral fat (r = -0.35), extremity fat (r = 0.37), insulin resistance (HOMA-IR) (r = -0.28), nucleoside reverse transcriptase inhibitor (NRTI) use (r = -0.32), and high-density lipoprotein (HDL) (r = 0.41) using bivariate analysis (all P < 0.01). The association with HDL weakened but remained significant on multivariate analysis (standard beta = 0.29, P = 0.01). However, the association of adiponectin with HOMA-IR became nonsignificant after adjusting for NRTI use (standard beta = -0.15, P = 0.12), suggesting that changes in adiponectin levels may underlie the effect of NRTI use on insulin resistance. The associations of adiponectin with triglycerides and HOMA-IR were also slightly weakened after adjusting for visceral and extremity fat, indicating that adiponectin may, in part, mediate the effect of FR on triglycerides and insulin resistance. This study indicates that adiponectin is inversely correlated with abdominal visceral fat mass, serum triglycerides, and insulin resistance and is directly correlated with HDL and extremity fat in a sample of HIV-infected patients treated with HAART. The results also indicate that NRTI use may worsen insulin resistance by decreasing adiponectin levels. Thus, adiponectin replacement may be a potential treatment option to ameliorate the metabolic changes observed in this patient population.

Topics: Abdomen; Adiponectin; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Cross-Sectional Studies; Female; HIV-Associated Lipodystrophy Syndrome; Humans; Hypertriglyceridemia; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Multivariate Analysis; Proteins

Despite evidence for the role of adipocyte-derived hormones in insulin resistance, little is known about their levels in human lipodystrophic states. We examined the relationships of plasma leptin and adiponectin levels to fat distribution and insulin sensitivity in the HIV lipodystrophy syndrome.. Cross-sectional study. HIV primary care practices. HIV-infected men with (n=13) and without (12) lipodystrophy and healthy uninfected controls (12).. Plasma adiponectin and leptin levels were measured in the fasting state. Body composition was assessed by physical examination, dual-energy x-ray absorptiometry and computed tomography. Insulin sensitivity (S(I)) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test.. Leptin levels were significantly higher in HIV-infected men with lipodystrophy as compared to HIV-infected controls (5.2 vs 3.0 ng/ml, P=0.01). Across the entire study population, leptin levels were positively correlated with measures of general adiposity. In the HIV-infected patients, leptin levels were negatively correlated with S(I) after adjustment for fat mass (r=-0.38, P=0.07). Adiponectin levels were significantly lower in HIV-infected men with lipodystrophy as compared to both HIV-infected and healthy controls (1.6 vs 3.4 microg/ml, P<0.05 and 1.6 vs 6.7 microg/ml, P<0.001, respectively). Adiponectin levels, after adjustment for fat mass, were correlated with measures of fat distribution. Finally, in the HIV-infected patients, adiponectin levels were significantly and positively correlated with S(I) after adjustment for fat mass (r=0.75, P < or = 0.001), and adiponectin level was also an independent determinant of S(I).. Plasma leptin and adiponectin levels are altered in the HIV lipodystrophy syndrome. Adiponectin deficiency may play a role in the insulin resistance associated with HIV lipodystrophy.

Topics: Adipocytes; Adiponectin; Adult; Body Composition; Body Mass Index; Cross-Sectional Studies; Glucose Tolerance Test; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Proteins

Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART).. We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index.. The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease.. These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Apolipoproteins A; Apolipoproteins B; C-Reactive Protein; Cholesterol; Cytokines; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Proteins; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Regression Analysis; Triglycerides; Tumor Necrosis Factor-alpha

Peripheral fat loss, or lipoatrophy, has been reported as an emerging complication of long-term antiretroviral regimens, mainly when nucleoside analogues are included. However, lipoatrophy does not develop in the majority of nucleoside inhibitor-treated patients, leading to the investigation of factors other than drug effects alone as potential contributors to this complication. We conducted a retrospective cohort study study and analysis of repository plasma samples taken from HIV-infected patients being treated with their initial antiretroviral regimen. CD4 cell count and plasma tumor necrosis factor (TNF), soluble TNF receptors, and leptin levels were assessed and correlated with the development of lipoatrophy. The most significant treatment-related factor in this study of patients on their first drug regimen was duration of antiretroviral therapy, rather than type of nucleoside inhibitor treatment. No association was found between lipoatrophy and specific nucleoside inhibitors, including zidovudine and stavudine. A significant association between lipoatrophy was found for 2 nondrug risk factors: older age and lower pretherapy body mass index. Our results emphasize the need for keeping in mind the role of host factors in the generation of lipoatrophy.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Integration Host Factors; Leptin; Male; Middle Aged; Retrospective Studies; Stavudine; Zidovudine

In this study, we sought to determine the relationship between serum levels of leptin and adiponectin (Acrp30) in patients with HIV-associated lipodystrophy (HIV-LD). Three groups of subjects were studied; HIV-positive subjects with lipodystrophy (HIV-LD; n = 22), HIV-positive subjects without lipodystrophy (HIV; n = 17), and ethnicity- and body mass index-matched healthy control subjects (n = 20). Although total body fat from dual energy x-ray absorptiometry was similar in all three groups, the HIV-LD group had a significantly lower mean proportion of body fat in the limbs +/- SEM (37.2% +/- 2.2%) than either controls (49.8% +/- 1.5%) or HIV subjects (45.7% +/- 2.0%). The HIV-LD group also had the lowest mean insulin sensitivity +/- SEM (5.11 +/- 0.59 mg of glucose/[kg of lean body mass. min] vs. 10.2 +/- 0.72 mg of glucose/[kg of lean body mass. min] in controls and 8.64 +/- 0.69 mg of glucose/[kg of lean body mass. min] in the HIV group). Leptin levels were similar in all three groups and were significantly correlated to total body fat (r = 0.86; p <.001), but these levels did not correlate with either insulin sensitivity or limb fat. Mean Acrp30 levels +/- SEM were lowest in the HIV-LD group (5.43 +/- 0.44 microg/mL vs. 11.2 +/- 1.4 microg/mL in the HIV group and 14.9 +/- 1.8 microg/mL in control subjects). Further, Acrp30 levels were positively correlated with insulin sensitivity (r = 0.610; p <.001) and limb fat (r = 0.483; p <.001). However, the correlation between limb fat and insulin sensitivity disappeared when Acrp30 level and other potential mediators were removed from the association, suggesting that a deficiency in Acrp30 in subjects with HIV-LD may be part of the mechanism for the reduced insulin sensitivity.

Topics: Adiponectin; Adult; Body Composition; Body Mass Index; CD4 Lymphocyte Count; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Logistic Models; Male; Middle Aged; Proteins; Viral Load