Antiretroviral-Related Adipocyte Dysfunction and Lipodystrophy in HIV-Infected Patients: Alteration of the PPARγ-Dependent Pathways

Lipodystrophy and metabolic alterations are major complications of antiretroviral therapy in HIV-infected patients. In vitro studies using cultured murine and human adipocytes revealed that some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were implicated to a different extent in adipose cell dysfunction and that a chronic incubation with some PIs decreased mRNA and protein expression of PPARγ. Defective lamin A maturation linked to PI inhibitory activity could impede the nuclear translocation of SREBP1c, therefore, reducing PPARγ expression. Adipose cell function was partially restored by the PPARγ agonists, thiazolidinediones. Adverse effects of PIs and NRTIs have also been reported in macrophages, a cell type that coexists with, and modulates, adipocyte function in fat tissue. In HIV-infected patients under ART, a decreased expression of PPARγ and of PPARγ-related genes was observed in adipose tissue, these anomalies being more severe in patients with ART-induced lipoatrophy. Altered PPARγ expression was reversed in patients stopping PIs. Treatment of patients with agonists of PPARγ could improve, at least partially, the subcutaneous lipoatrophy. These data indicate that decreased PPARγ expression and PPARγ-related function, resulting from ART-induced adipose tissue toxicity, play a central role in HIV-related lipoatrophy and metabolic consequences

Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

Les traitements antirétroviraux de l’infection par le VIH sont responsables d’effets secondaires parfois sévères qui touchent en priorité le tissu adipeux, modifiant sa localisation (lipodystrophie avec lipoatrophie périphérique et hypertrophie centrale) et les paramètres du métabolisme glucido-lipidique (dyslipidémie, diabète). Les deux principales classes thérapeutiques, inhibiteurs de protéase et analogues nucléosidiques, sont délétères sur ces paramètres par des mécanismes différents mais qui convergent sur le tissu adipeux. Certaines des molécules de ces deux classes modifient profondément sa différenciation, son métabolisme, sa fonction mitochondriale et l’équilibre des hormones (leptine, adiponectine) et cytokines (TNFα, IL-6) qu’il sécrète. Ce syndrome de lipodystrophie induit un risque cardiovasculaire et de stéatohépatite grevant le pronostic vital. Le traitement reste difficile chez les patients atteints et privilégie le remplacement des molécules les plus délétères par des molécules antirétrovirales plus récentes et moins agressives sur le tissu adipeux.HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFα, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue

HIV-associated lipodystrophy: from fat injury to premature aging

Combination antiretroviral therapy (cART) against HIV infection dramatically reduces AIDS-related morbidity. However, many patients under cART display HIV-associated lipodystrophy. Moreover, some develop early agerelated comorbidities. Thymidine analog reverse transcriptase inhibitors (tRNTIs) are mainly responsible for peripheral lipoatrophy, and protease inhibitors (PIs) for fat hypertrophy and metabolic complications. Longterm HIV infection probably also causes fat alterations. Severe mitochondrial toxicity and oxidative stress cause lipoatrophy, whereas the hypertrophy of upper body fat depots could result from mild oxidative stress, cortisol activation and inflammation. The metabolic complications associated with lipodystrophy are responsible for increased cardiovascular and hepatic risks and could also participate in premature aging. We propose that adipose tissue injury by HIV and cART induces fat hypertrophy or atrophy and contributes to premature aging

PLoS One

AIM: Metabolic risk factors are poorly documented for the first generation of young adults who have lived with HIV since childhood. We compared their metabolic profile with that of adults of same age from the general population. METHODS: We conducted a cross-sectional analysis of data from two populations: (1) COVERTE (ANRS-CO19), a French national cohort of 18 to 30-year-old patients HIV-infected since childhood, and (2) ENNS, a national cross-sectional population-based household survey on nutrition. Body mass index (BMI), blood pressure, waist circumference, fasting glucose, triglycerides, and HDL-, LDL- and total cholesterol were measured in both studies. Direct standardization on overweight and education level and logistic regression were used to compare the prevalence of metabolic abnormalities between the two populations. RESULTS: Data from 268 patients from COVERTE and 245 subjects from ENNS were analyzed. Tobacco use was similar in both groups. HIV-infected patients had increased mean waist-to-hip ratio and triglycerides to HDL-cholesterol ratio and decreased mean HDL-cholesterol as compared to their counterparts from the general population in both genders. In HIV-infected patients, metabolic syndrome was identified in 13.2% of men (95% confidence interval [CI]: 7.1-19.2) and 10.4% (95% CI: 5.4-15.3) of women versus 10.6% (95%CI: 1.5-19.7) and 1.7% (95%CI: 0-4.1) in subjects from the general population, respectively. CONCLUSION: Young adults infected with HIV since childhood had a higher prevalence of dyslipidemia and metabolically detrimental fat distribution than adults of same age of the general population, supporting close monitoring for cardiometabolic diseases

Trend analysis of greenhouse gases over Europe measured by a network of ground-based remote FTIR instruments

This paper describes the statistical analysis of annual trends in long term datasets of greenhouse gas measurements taken over ten or more years. The analysis technique employs a bootstrap resampling method to determine both the long-term and intra-annual variability of the datasets, together with the uncertainties on the trend values. The method has been applied to data from a European network of ground-based solar FTIR instruments to determine the trends in the tropospheric, stratospheric and total columns of ozone, nitrous oxide, carbon monoxide, methane, ethane and HCFC-22. The suitability of the method has been demonstrated through statistical validation of the technique, and comparison with ground-based in-situ measurements and 3-D atmospheric models.Peer reviewe