Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
Open accessAbstract
OBJECTIVE: Breakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors. METHODS: In the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. RESULTS: ART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. CONCLUSION: The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.
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In mice on high-fat diet, administration of efavirenz and emtricitabine decreased glucose tolerance and increased insulin resistance.
“When mice fed on a high‐fat diet were also administered with the NNRTI efavirenz and NRTI emtricitabine, there was a decrease in glucose tolerance and increase in insulin resistance (Pepin et al, 2018).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Pepin et al, 2018
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“contributed to further macrophage infiltration and polarization to the M1 phenotype, accompanied by enhanced inflammation (100).”
BackgroundAdipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV
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Oeing, C. U., Pepin, M. E., Saul, K. B., Agircan, A. S., Assenov, Y., Merkel, T. S., Sedaghat‐Hamedani, F., Weis, T., Meder, B., Guan, K., et al. (2023) · Basic Research in Cardiology · doi:10.1007/s00395-022-00954-3 · Cited by 15 · see citing works
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Obesity in HIV infection: host-pathogen interaction
Savinelli, S., Kelly, N. E. W., Feeney, E. R., O'Shea, D. B., Hogan, A. E., Overton, E. T., LANDAY, A. L., & Mallon, P. W. G. (2022) · AIDS · doi:10.1097/qad.0000000000003281 · Cited by 12 · see citing works
MicroRNA Profiling in HIV-Infected South African Women with Gestational Diabetes Mellitus
Pheiffer, C., Dias, S. C., Rheeder, P., & Adam, S. (2019) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-019-00404-2 · Cited by 10 · see citing works
The SETD6 Methyltransferase Plays an Essential Role in Hippocampus-Dependent Memory Formation
Webb, W. M., Irwin, A. B., Pepin, M. E., Henderson, B. W., Huang, V., Butler, A. A., Herskowitz, J. H., Wende, A. R., Cash, A. E., & Lubin, F. D. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.022 · Cited by 9 · see citing works
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Exploring the Relation Between Diabetes and HIV: A Narrative Review
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“Type 2 diabetes and metabolic derangement have been connected to HIV infection and ART [5].”
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The miRNomics of antiretroviral therapy-induced obesity
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“Changes in daily average dietary intake have also been shown to aid in excessive weight gain in people with HIV (Bailin et al. 2024; Hernandez et al. 2017; Pepin et al. 2018).”
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“Evidence suggests that HIV-infected patients frequently exhibit a higher prevalence of insulin resistance compared to the general population, placing them at an increased risk for prediabetes and T2DM [80].”
The Bi-directional Relationship Between Childhood Malnutrition and HIV/AIDS
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“ART prevent them from being routinely used by patients undergoing ART (41).”
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Acquired immunodeficiency syndrome (AIDS)
Karim, Q. A., Singh, U., Baxter, C., & Karim, S. S. A. (2021) · doi:10.1093/med/9780198816805.003.0071
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- Authors
- Pepin, M. E., Padgett, L. E., McDowell, R. E., Burg, A. R., Brahma, M. K., Holleman, C., Kim, T., Crossman, D., Kutsch, O., Tse, H. M., Wende, A. R., & Habegger, K. M.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Wende, Adam R.
- Habegger, Kirk M.
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 12
- Pages
- 48-61
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6001921
- OpenAlex
- W2802315060
- Cited by
- 25
- References
- 60
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Environmental Protection
- National Institutes of Health (HD071866, P30 AI027767)
- National Heart, Lung, and Blood Institute (R01 HL133011)
- American Diabetes Association (R01 DK112934, NIDDK R01 DK099550, 7-12-CD-11)
- Center for AIDS Research, Emory University
- Topics
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- antiretroviral therapy, high-fat diet, obesity, impaired glucose tolerance, insulin resistance, metabolic syndrome, adipose tissue inflammation, macrophages, energy balance, HIV, granulocyte migration, kinomics, epididymal adipose tissue
- MeSH terms
- Animals, Cells, Cultured, Insulin Resistance, Macrophages, Mice, Inbred C57BL, Obesity, Glucose Intolerance, Anti-Retroviral Agents, Mice, Adipose Tissue, White, Diet, High-Fat, Transcriptome
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