The Integrase Inhibitors Dolutegravir and Raltegravir Exert Proadipogenic and Profibrotic Effects and Induce Insulin Resistance in Human/Simian Adipose Tissue and Human Adipocytes
| Autor: | Christine Bourgeois, Delphine Desjardins, Claire Lagathu, Jennifer Gorwood, Guillaume Pourcher, Roger Le Grand, Frédéric Charlotte, Christine Katlama, Cindy Rose, Olivier Lambotte, Véronique Béréziat, Valérie Pourcher, Romain Morichon, Michael Atlan, Bruno Fève, Matthieu Mantecon, Jacqueline Capeau |
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| Přispěvatelé: | Sorbonne Université (SU) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Microbiology (medical) medicine.medical_specialty Pyridones 030106 microbiology Adipose tissue HIV Infections Integrase Inhibitors [SDV.BC]Life Sciences [q-bio]/Cellular Biology Piperazines 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Fibrosis Raltegravir Potassium Internal medicine Adipocyte Drug Resistance Viral Oxazines Adipocytes medicine Humans HIV Integrase Inhibitors 030212 general & internal medicine ComputingMilieux_MISCELLANEOUS Adiponectin business.industry medicine.disease Raltegravir 3. Good health Infectious Diseases Endocrinology Adipose Tissue chemistry Adipogenesis Dolutegravir Insulin Resistance business Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Clinical Infectious Diseases Clinical Infectious Diseases, Oxford University Press (OUP), 2020, ⟨10.1093/cid/ciaa259⟩ |
| ISSN: | 1537-6591 1058-4838 |
| Popis: | Background Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function. Methods Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir. Results We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs’ proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance. Conclusions Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV. |
| Databáze: | OpenAIRE |
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