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
Abstract
:1. Introduction
2. Materials and Methods
2.1. Adipose Tissue Samples from Macaques
2.2. Isolation and Differentiation of ASCs
2.3. Protein Extraction and Western Blotting
2.4. Protein Secretion into the Cell Culture Media
2.5. RNA Isolation and Quantitative PCR
2.6. Oxidative Stress and Mitochondrial Dysfunctions
2.7. Oxygen Consumption Measurements
2.8. Lipid Metabolism
2.9. Statistical Analysis
3. Results
3.1. SCAT and VAT from SIV-Infected Dolutegravir-Treated Macaques Display Higher Levels of PPARG and Profibrotic Gene Expression but Lower Levels of Beige Marker Gene Expression
3.2. INSTIs Are Associated with Elevated Lipogenic Gene Expression and Insulin Resistance in Beige Adipocytes
3.3. Dolutegravir and Bictegravir Inhibit Beige Differentiation
3.4. Dolutegravir and Bictegravir Are Associated with Impaired Mitochondrial Integrity in Beige Adipocytes
3.5. Dolutegravir Enhances the Expression of Profibrotic Genes in Beige Adipocytes
3.6. Treatment with Dolutegravir Is Associated with Elevated Expression of HIF1A, Which Is Causally Related to Beiging Inhibition and Fibrosis In Vivo and In Vitro
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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HIF1A | |||||
---|---|---|---|---|---|
SCAT | VAT | ||||
r | p | r | p | ||
Beiging | PRDM16 | −0.665 | 0.018 | −0.188 | 0.251 |
Fibrosis | COL6A1 | 0.468 | 0.054 | 0.655 | 0.003 |
COL1A2 | 0.021 | 0.475 | 0.527 | 0.027 | |
TGFB1 | 0.617 | 0.012 | 0.744 | <0.001 | |
Adipogenesis | PPARG | 0.622 | 0.015 | 0.073 | 0.395 |
HIF1A | |||
---|---|---|---|
r | p | ||
Beiging | PRDM16 | −0.410 | 0.009 |
UCP1 | −0.435 | 0.008 | |
DIO2 | −0.663 | <0.001 | |
Fibrosis | COL6A1 | −0.040 | 0.412 |
COL1A1 | 0.286 | 0.059 | |
COL1A2 | 0.559 | <0.001 | |
LOX | 0.606 | <0.001 | |
ACTA2 | 0.561 | <0.001 | |
TGFB1 | 0.123 | 0.250 | |
DDR1 | 0.480 | 0.002 | |
Lipid metabolism | PPARG | 0.05 | 0.397 |
FABP4 | 0.438 | 0.006 | |
Oil-Red-O | 0.357 | 0.043 |
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Ngono Ayissi, K.; Gorwood, J.; Le Pelletier, L.; Bourgeois, C.; Beaupère, C.; Auclair, M.; Foresti, R.; Motterlini, R.; Atlan, M.; Barrail-Tran, A.; et al. 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. Cells 2022, 11, 1841. https://doi.org/10.3390/cells11111841
Ngono Ayissi K, Gorwood J, Le Pelletier L, Bourgeois C, Beaupère C, Auclair M, Foresti R, Motterlini R, Atlan M, Barrail-Tran A, et al. 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. Cells. 2022; 11(11):1841. https://doi.org/10.3390/cells11111841
Chicago/Turabian StyleNgono Ayissi, Kenza, Jennifer Gorwood, Laura Le Pelletier, Christine Bourgeois, Carine Beaupère, Martine Auclair, Roberta Foresti, Roberto Motterlini, Michael Atlan, Aurélie Barrail-Tran, and et al. 2022. "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" Cells 11, no. 11: 1841. https://doi.org/10.3390/cells11111841