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Tumour necrosis factor alpha in fat redistribution syndromes associated with combination antiretroviral therapy in HIV‐1‐infected patients: potential role in subcutaneous adipocyte apoptosis
Author(s) -
Domingo P.,
Vidal F.,
Domingo J. C.,
Veloso S.,
Sambeat M. A.,
Torres F.,
Sirvent J. J.,
Vendrell J.,
MatiasGuiu X.,
Richart C.
Publication year - 2005
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2005.01576.x
Subject(s) - tunel assay , adipocyte , apoptosis , terminal deoxynucleotidyl transferase , endocrinology , medicine , tumor necrosis factor alpha , immunology , biology , adipose tissue , biochemistry
Background The pathogenesis of fat redistribution syndromes (FRS) observed in the setting of highly active antiretroviral therapy (HAART) for the treatment of HIV‐1‐infection remains elusive. A dysregulation of the tumour necrosis factor alpha (TNF‐α) system occurs in HIV‐infected patients with FRS. Materials and methods The study looked at both the in vivo and in vitro relationship between TNF‐α and the degree of subcutaneous adipocyte apoptosis in 60 HIV‐1‐infected patients on HAART with FRS, another 60 HIV‐1‐infected patients on HAART without FRS and 60 uninfected control patients. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP (deoxyuridine 5′‐triphosphate)‐digoxigenin Nick End Labelling (TUNEL) method. Soluble receptors of TNF‐α were determined by the sandwich enzyme immunoassay technique. The in vitro viability was assessed by staining with 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5 diphenyltetrazolium bromide (MTT) and apoptosis by TUNEL. Results HIV‐1‐infected patients with FRS had significantly higher degrees of subcutaneous adipocyte apoptosis than those without FRS ( P = 0·0001) and uninfected controls ( P < 0·0001). There was a statistically significant association between serum levels of soluble TNF‐α receptors #1 and #2 and the degree of subcutaneous adipocyte apoptosis in patients with and without FRS ( P < 0·0001 for both receptors). In vitro , the addition of TNF‐α (10 ng mL −1 ) to an adipocyte culture embedded with indinavir, either alone or in clinically relevant combinations with stavudine (d4T) and lamivudine (3TC), significantly decreased adipocyte viability ( P = 0·0001) and increased adipocyte apoptosis ( P < 0·0001) with respect to that observed with the addition of antiretrovirals alone. Conclusions TNF‐α plays a significant role in subcutaneous adipocyte apoptosis, which occurs in the setting of FRS in HIV‐1‐infected patients on highly active antiretroviral therapy.