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Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes
For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes i...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180037/ https://www.ncbi.nlm.nih.gov/pubmed/35681536 http://dx.doi.org/10.3390/cells11111841 |
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author | Ngono Ayissi, Kenza Gorwood, Jennifer Le Pelletier, Laura Bourgeois, Christine Beaupère, Carine Auclair, Martine Foresti, Roberta Motterlini, Roberto Atlan, Michael Barrail-Tran, Aurélie Le Grand, Roger Desjardins, Delphine Fève, Bruno Lambotte, Olivier Capeau, Jacqueline Béréziat, Véronique Lagathu, Claire |
author_facet | Ngono Ayissi, Kenza Gorwood, Jennifer Le Pelletier, Laura Bourgeois, Christine Beaupère, Carine Auclair, Martine Foresti, Roberta Motterlini, Roberto Atlan, Michael Barrail-Tran, Aurélie Le Grand, Roger Desjardins, Delphine Fève, Bruno Lambotte, Olivier Capeau, Jacqueline Béréziat, Véronique Lagathu, Claire |
author_sort | Ngono Ayissi, Kenza |
collection | PubMed |
description | For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance. |
format | Online Article Text |
id | pubmed-9180037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91800372022-06-10 Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes Ngono Ayissi, Kenza Gorwood, Jennifer Le Pelletier, Laura Bourgeois, Christine Beaupère, Carine Auclair, Martine Foresti, Roberta Motterlini, Roberto Atlan, Michael Barrail-Tran, Aurélie Le Grand, Roger Desjardins, Delphine Fève, Bruno Lambotte, Olivier Capeau, Jacqueline Béréziat, Véronique Lagathu, Claire Cells Article For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance. MDPI 2022-06-04 /pmc/articles/PMC9180037/ /pubmed/35681536 http://dx.doi.org/10.3390/cells11111841 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ngono Ayissi, Kenza Gorwood, Jennifer Le Pelletier, Laura Bourgeois, Christine Beaupère, Carine Auclair, Martine Foresti, Roberta Motterlini, Roberto Atlan, Michael Barrail-Tran, Aurélie Le Grand, Roger Desjardins, Delphine Fève, Bruno Lambotte, Olivier Capeau, Jacqueline Béréziat, Véronique Lagathu, Claire Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title | Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title_full | Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title_fullStr | Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title_full_unstemmed | Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title_short | Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes |
title_sort | inhibition of adipose tissue beiging by hiv integrase inhibitors, dolutegravir and bictegravir, is associated with adipocyte hypertrophy, hypoxia, elevated fibrosis, and insulin resistance in simian adipose tissue and human adipocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180037/ https://www.ncbi.nlm.nih.gov/pubmed/35681536 http://dx.doi.org/10.3390/cells11111841 |
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