Underlying mechanisms: adipocytes and cytokines
Simon Collins, HIV i-Base
An excellent overview of the recent basic science presented at the workshop, particularly relating to nucleoside therapy, was provided by Professor Capeau at the subsequent IAS conference.
Many of the presentations focused on the effect of HIV treatment on insulin resistance, and altered cytokines that in turn leads to reduced ability to store fat and adipocyte apoptosis. 
Several studies focused on the endocrine function of adipocytes in secreting the adipocytokines leptin and adiponectin which control insulin resistance in liver and muscle tissue. Reduced adiponectin was shown to increase insulin resistance and adiponectin partially reversed – and when given together with leptin totally reversed – insulin resistance in lipoatrophic mice.
Adiponectin was also independently and inversely associated with insulin resistance and significantly associated with increased abdominal and reduced peripheral fat in results from a study of 134 HIV-positive patients presented by Khatami and colleagues from UCSF. 
Frayn focused on a complementary role of adipose tissue as a ‘buffer’ to the daily intake of fatty acids in the same way that liver ‘buffers’ the intake of carbohydrates. In the case of fat accumulation, adipocytes are already swollen and less active than smaller cells and with lipoatrophy there may not be sufficient adipose tissue to cope with incoming fat, and both would account for increased plasma lipidaemia. 
A direct effect on fat cells – through altered differentiation (shown with some PIs through interfering with SREBP-1 signalling, and SREBP-1 controls adipogenesis in the liver) or decreased mitochondrial function (shown with nucleosides).
Deveaud and colleagues showed that AZT decreased mitochondrial DNA and cytochrome oxidase levels in subcutaneous fat but not visceral fat in rats, due to slower mitochondrial activity in visceral fat.  Other potential mechanisms besides mitochondrial toxicity linked to nucleoside toxicity that were suggested included: certain metabolites of AZT and d4T decrease body fat and increase fatty acid oxidation ; altered viability and function of immature (mouse) adipocytes ; and decreased lipid accumulation from AZT and d4T (but not abacavir, ddI or 3TC) in cultured cells. 
Capeau and colleagues reported increased apoptosis, percentage of fibrosis and number of cells (as a compensatory reaction to apoptosis of fat cells) in ten lipoatrophic patients compared to six HIV-negative controls and that this correlated with increases in cytokines IL-6 and TNF-alpha, and negatively with differentiation markers SREBP-1 and C/EBP-alpha. 
This article is part of a longer report from the 5th International Workshop on Adverse Drug Reactions and Lipodystrophy, 8-11 July 2003, Paris. Part two of this report.
Unless otherwise stated, all abstracts refer to the programme and abstracts from the 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 8-11 July 2003, Paris and are published in Antiviral Therapy Volume 8 issue 4.
- Capeau J, Caron M, Auclair M et al – Effects of NRTI on differentiation, response to insulin and apoptosis in cultured adipocytes. 2nd IAS Conference on HIV Pathogenesis and Treatment, 13–16 July, Paris. Abstract 206.
- Yamauchi T – The roles and mechanisms of adipocytokines in insulin resistance. Abstract P3.
- Khatami H, Mulligan K, Lo JC et al – Role of adipocytokines and body fat distribution in insulin resistance in HIV infection. Abstract 44
- Frayn K – Adipose tissue and insulin resistance. Abstract P2.
- Deveaud C, Beauvoit B, Rogoulet M – Effects of the treatment by nucleoside reverse transcriptase inhibitors on mitochondrial function of superficial and deep adipose tissues of rats. Abstract 50.
- Maisonneuve C, Begriche K – Effects of AZT and d4T on ketone bodies and lipids in mice: possible role of beta-aminoisobutyric acid, a catabolite of thymine. Abstract 20.
- Flint OP, Mulvey R, Elosua C et al – The effect of tenofovir, zidovudine and stavudine on adipocyte mitochondrial DNA, viability and lipid metabolism. Abstract 65.
- 8. Caron M, Auclair M, Kornprobst M et al – Effects of NRTI on differentiation, response to insulin and apoptosis in cultured adipocytes. Abstract 10.
- 9. Capeau J, Bastard JP, Cervera P et al – Increased IL-6 and TNF expression is related to increased apoptosis and decreased differentiation in adipose tissue from patients with HIV-related lipoatrophy. Abstract 9.