Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Abstract

Although it is well accepted that treatment with some nucleoside reverse transcriptase inhibitors modifies both fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examined whether a decrease in oxidative capacity, induced by a chronic oral administration of 3-azido-3-deoxythymidine (AZT) in rats, could be associated with an alteration of the lipogenic capacity of white adipose tissues. The impact of obesity as a factor was then evaluated. Results showed that AZT treatment induced differential effects depending on anatomical localization. Indeed, in the inguinal adipose tissue, the specific activities of cytochrome c oxidase and fatty acid synthase, two ratecontrolling enzymes in energy and lipogenic metabolisms, respectively, both decreased under AZT treatment, thus leading to a lowered cell lipid accumulation. Moreover, the AMP-activated protein kinase phosphorylation level tended to increase, thus implying that AZT causes an energy imbalance. Furthermore, the inguinal tissue of obese rats presented a sensitivity to AZT treatment that was higher than that of lean rats. In contrast, for epididymal tissue, no significant change in all these parameters could be detected under AZT treatment, regardless of the nutritional status of the animals. Taken together, these data demonstrate differential effects of AZT on subcutaneous adipose tissue and visceral white adipose tissue. It could be considered that the chronic decreases in energy and lipogenic metabolism of inguinal adipocyte, consecutive to AZT treatment, may lead, in the long term, to adipose tissue atrophy.

Adipose tissue inflammation and altered adipokine and cytokine production in antiretroviral therapy-associated lipodystrophy

“…For example, investigations by Petit and colleagues [70] have revealed that NRTIinduced mitochondrial DNA depletion in cultured human adipose tissue is accompanied by a proportional reduction in ATP production and mitochondrial respiration rates, indicating that even small changes in adipocyte mitochondrial DNA levels can have important effects on cell function [70]. Similar results have been obtained in studies of zidovudine-treated rats, in which adipose tissue mitochondrial DNA depletion and respiratory function were highly correlated in the subcutaneous fat depot but not in visceral fat [71]. In this study, zidovudine was also found to activate AMP kinase, a key regulator of adipose energy status that seeks to conserve energy (in the form of ATP) by limiting fatty acid efflux from adipocytes and favouring local fatty acid oxidation [72].…”

Impaired expression of testicular androgen receptor and collagen fibers in the testis of diabetic rats under HAART: the role of Hypoxis hemerocallidea

“…HAART with HH induced negative observational changes in the body weight of experimental animals, mostly marked in the diabetic + HAART + HH (100 and 200 mg/kg) animals. While loss of weight may be associated with induction of diabetes, initiation of HAART may as well contribute to the low pace of weight gain due to other metabolic activities relative to lipid and sugar [41].…”

Potential Role of IL-18 in the Immunopathogenesis of AIDS, HIVAssociated Lipodystrophy and Related Clinical Conditions

“…For example, AZT is known to inhibit replication of mitochondrial DNA and biogenesis of mitochondria in adipocytes. Decreased numbers of mitochondria adversely affect functions of the adipose tissues [118]. Similarly, HIV protease inhibitors (PI) often cause cellular stress, inhibit the normal differentiation process of adipocytes and reduce fat storing capacity of the body [119].…”