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Updated: Feb 23, 2026
Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes
Eyone Jones1, Pavel Mazirka1, Margaret A McNurlan1
1Eyone Jones, Department of Surgery, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.
Aim:
To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome.
Methods:
Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase (GP DH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher's Least Significant Difference test.
Results:
Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI (14% at 48 h, P < 0.001) and PI + NRTI (19% at 48 h, P < 0.001) with additional suppression when ritonavir (RTV) was added (26% at 48 h). The drug combination of atazanavir (ATV) + RTV + emtricitabine (FTC) + tenofovir (TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity (64%) or lipid accumulation (39%), P < 0.001. Combining NRTIs with a PI (ATV + FTC + TDF) significantly suppressed differentiation (GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added (ATV + FTC + TDF + RTV, P < 0.001).
Conclusion:
Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.
Insights
Highly-active antiretroviral therapy (HAART) combinations significantly inhibit preadipocyte proliferation and differentiation, contributing to lipodystrophy syndrome. This highlights potential risks associated with potent HIV treatments.
Area of Science:
- Cell Biology
- Pharmacology
- Virology
Background:
- Highly-active antiretroviral therapy (HAART) is crucial for managing HIV/AIDS.
- Lipodystrophy syndrome, characterized by abnormal fat distribution, is a known side effect of HAART.
- The precise mechanisms linking HAART to lipodystrophy remain under investigation.
Purpose of the Study:
- To elucidate the cellular mechanisms by which multi-drug HAART contributes to lipodystrophy syndrome.
- To assess the impact of different classes of antiretroviral drugs on preadipocyte function.
Main Methods:
- Preadipocytes from healthy donors were cultured and exposed to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination.
- Cell proliferation was measured using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay.
- Cell differentiation was assessed by measuring glycerol-3-phosphate dehydrogenase (GP DH) activity and quantifying Oil Red O staining for intracellular lipid accumulation.
Main Results:
- Combined NNRTI + NRTI and PI + NRTI regimens significantly inhibited preadipocyte proliferation.
- The combination of atazanavir (ATV) + ritonavir (RTV) + emtricitabine (FTC) + tenofovir (TDF) demonstrated the greatest inhibitory effect on proliferation.
- Efavirenz + FTC + TDF significantly reduced preadipocyte differentiation, as evidenced by decreased GPDH activity and lipid accumulation. Combination therapy with NRTIs and PIs, especially with RTV boosting, further suppressed differentiation.
Conclusions:
- Combination antiretroviral therapy exhibits a substantially greater inhibitory effect on preadipocyte proliferation and differentiation compared to single-drug regimens.
- These findings suggest that the potent effects of multi-drug HAART on adipocyte precursors may underlie the development of lipodystrophy syndrome.
- Understanding these mechanisms is vital for developing safer and more effective HIV treatment strategies.
