Circulating Concentration of Adiponectin and Its Expression in Subcutaneous Adipose Tissue in Patients with Highly Active Antiretroviral Therapy-Associated Lipodystrophy

Highly active antiretroviral therapy (HAART) has improved the prognosis of human immunodeficiency virus (HIV)-infected patients but is associated with severe adverse events, such as lipodystrophy and insulin resistance. Rosiglitazone did not increase subcutaneous fat in patients with HAART-associated lipodystrophy (HAL) in a randomized, double-blind, placebo-controlled trial, although it attenuated insulin resistance and decreased liver fat content. The aim of this study was to examine effects of rosiglitazone on gene expression in subcutaneous adipose tissue in 30 patients with HAL. The mRNA concentrations in subcutaneous adipose tissue were measured using real-time PCR. Twenty-four-week treatment with rosiglitazone (8 mg/day) compared with placebo significantly increased the expression of adiponectin, peroxisome proliferator-activated receptor-γ (PPARγ), and PPARγ coactivator 1 and decreased IL-6 expression. Expression of other genes involved in lipogenesis, fatty acid metabolism, or glucose transport, such as acyl-CoA synthase, adipocyte lipid-binding protein, CD45, fatty acid transport protein-1 and -4, GLUT1, GLUT4, keratinocyte lipid-binding protein, lipoprotein lipase, PPARδ, and sterol regulatory element-binding protein-1c, remained unchanged. Rosiglitazone also significantly increased serum adiponectin concentration. The change in serum adiponectin concentration was inversely correlated with the change in fasting serum insulin concentration and liver fat content. In conclusion, rosiglitazone induced significant changes in gene expression in subcutaneous adipose tissue and ameliorated insulin resistance in patients with HAL. Increased expression of adiponectin might have mediated most of the favorable insulin-sensitizing effects of rosiglitazone in these patients.

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Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90224.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. E85-E91 ◽

Cited By ~ 37

Author(s):

Ksenia Sevastianova ◽

Jussi Sutinen ◽

Katja Kannisto ◽

Anders Hamsten ◽

Matti Ristola ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Antiretroviral Therapy ◽

Highly Active Antiretroviral Therapy ◽

Liver Fat ◽

Adipose Tissue Inflammation ◽

Liver Fat Content ◽

Abdominal Adipose Tissue ◽

Highly Active ◽

Subcutaneous Abdominal Adipose Tissue

In this cross-sectional study, we sought to determine whether gene expression of macrophage markers and inflammatory chemokines in lipoatrophic subcutaneous abdominal adipose tissue and liver fat content are increased and interrelated in human immunodeficiency virus (HIV)-1-positive, highly active antiretroviral therapy (HAART)-treated patients with lipodystrophy (HAART+LD+; n = 27) compared with those without (HAART+LD−; n = 13). The study groups were comparable with respect to age, gender, and body mass index. The HAART+LD+ group had twofold more intra-abdominal ( P = 0.01) and 1.5-fold less subcutaneous ( P = 0.091) fat than the HAART+LD− group. As we have reported previously, liver fat was 10-fold higher in the HAART+LD+ compared with the HAART+LD− group ( P = 0.00003). Inflammatory gene expression was increased in HAART-lipodystrophy: CD68 4.5-fold ( P = 0.000013), tumor necrosis factor (TNF)-α 2-fold ( P = 0.0094), chemokine (C-C motif) ligand (CCL) 2 2.5-fold ( P = 0.0024), CCL3 7-fold ( P = 0.0000017), integrin αM (ITGAM) 3-fold ( P = 0.00067), epidermal growth factor-like module containing, mucin-like, hormone receptor-like (EMR)1 2.5-fold ( P = 0.0038), and a disintegrin and metalloproteinase domain (ADAM)8 3.5-fold ( P = 0.00057) higher in the HAART+LD+ compared with the HAART+LD− group. mRNA concentration of CD68 ( r = 0.37, P = 0.019), ITGAM ( r = 0.35, P = 0.025), CCL2 ( r = 0.39, P = 0.012), and CCL3 ( r = 0.54, P = 0.0003) correlated with liver fat content. In conclusion, gene expression of markers of macrophage infiltration and adipose tissue inflammation is increased in lipoatrophic subcutaneous abdominal adipose tissue of patients with HAART-associated lipodystrophy compared with those without. CD68, ITGAM, CCL2, and CCL3 expression is significantly associated with accumulation of liver fat.

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Epicardial Adipose Tissue is Related to Carotid Intima-Media Thickness and Visceral Adiposity in HIV-Infected Patients with Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome

Current HIV Research ◽

10.2174/157016207780077084 ◽

2007 ◽

Vol 5 (2) ◽

pp. 275-279 ◽

Cited By ~ 41

Author(s):

Gianluca Iacobellis ◽

Arya Sharma ◽

Adriano Pellicelli ◽

Benvenuto Grisorio ◽

Giorgio Barbarini ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Antiretroviral Therapy ◽

Highly Active Antiretroviral Therapy ◽

Epicardial Adipose Tissue ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Visceral Adiposity ◽

Media Thickness ◽

Highly Active

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Cellular Mechanism Underlying Highly-Active or Antiretroviral Therapy-Induced Lipodystrophy: Atazanavir, a Protease Inhibitor, Compromises Adipogenic Conversion of Adipose-Derived Stem/Progenitor Cells through Accelerating ER Stress-Mediated Cell Death in Differentiating Adipocytes

International Journal of Molecular Sciences ◽

10.3390/ijms22042114 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2114

Author(s):

Sadanori Akita ◽

Keiji Suzuki ◽

Hiroshi Yoshimoto ◽

Akira Ohtsuru ◽

Akiyoshi Hirano ◽

...

Keyword(s):

Adipose Tissue ◽

Antiretroviral Therapy ◽

Protease Inhibitor ◽

Er Stress ◽

Highly Active Antiretroviral Therapy ◽

Adipogenic Differentiation ◽

Cell Lineage ◽

Protein S ◽

Altered Expression ◽

Highly Active

Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).

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