Jennifer Gorwood1, Christine Bourgeois2, Valérie Pourcher3,4, Guillaume Pourcher5, Frédéric Charlotte6, Matthieu Mantecon1, Cindy Rose1, Romain Morichon1, Michael Atlan1,7, Roger Le Grand2, Delphine Desjardins2, Christine Katlama3,4, Bruno Fève1,8, Olivier Lambotte2,9, Jacqueline Capeau1, Véronique Béréziat1, Claire Lagathu1. 1. Sorbonne Université, Inserm Unité Mixte de Recherche S938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition, Paris, France. 2. Commissariat à l'Energie Atomique, Université Paris Sud 11, Inserm U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Fontenay-aux-Roses, France. 3. Assistance publique-Hôpitaux de Paris, Sorbonne Université, Hôpital Pitié-Salpêtrière, Service de maladies infectieuses et tropicales, Paris, France. 4. Sorbonne Université-Inserm, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France. 5. Obesity Center, Institut Mutualiste Montsouris, Paris Descartes University, Paris, France. 6. Assistance publique-Hôpitaux de Paris, Sorbonne Université, Hôpital Pitié-Salpêtrière, Service d'Anatomie Pathologique, Paris, France. 7. Assistance publique-Hôpitaux de Paris, Hôpital Tenon, Service de Chirurgie Plastique et Esthétique, Paris, France. 8. Assistance publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Pathologies de la Résistance à l'Insuline et de l'Insulino-Sensibilité, Service d'Endocrinologie, Diabétologie et Reproduction, Paris, France. 9. Assistance publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Kremlin-Bicêtre, France.
Abstract
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.
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.
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