Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance

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...

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Main Authors: Mark E. Pepin, Lindsey E. Padgett, Ruth E. McDowell, Ashley R. Burg, Manoja K. Brahma, Cassie Holleman, Teayoun Kim, David Crossman, Olaf Kutsch, Hubert M. Tse, Adam R. Wende, Kirk M. Habegger
Format: Article
Language:English
Published: Elsevier 2018-06-01
Series:Molecular Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877818302321
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author Mark E. Pepin
Lindsey E. Padgett
Ruth E. McDowell
Ashley R. Burg
Manoja K. Brahma
Cassie Holleman
Teayoun Kim
David Crossman
Olaf Kutsch
Hubert M. Tse
Adam R. Wende
Kirk M. Habegger
spellingShingle Mark E. Pepin
Lindsey E. Padgett
Ruth E. McDowell
Ashley R. Burg
Manoja K. Brahma
Cassie Holleman
Teayoun Kim
David Crossman
Olaf Kutsch
Hubert M. Tse
Adam R. Wende
Kirk M. Habegger
Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
Molecular Metabolism
author_facet Mark E. Pepin
Lindsey E. Padgett
Ruth E. McDowell
Ashley R. Burg
Manoja K. Brahma
Cassie Holleman
Teayoun Kim
David Crossman
Olaf Kutsch
Hubert M. Tse
Adam R. Wende
Kirk M. Habegger
author_sort Mark E. Pepin
title Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
title_short Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
title_full Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
title_fullStr Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
title_full_unstemmed Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
title_sort antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
publisher Elsevier
series Molecular Metabolism
issn 2212-8778
publishDate 2018-06-01
description 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. Keywords: Antiretroviral therapy, Obesity, Glucose intolerance, Adipose tissue inflammation, Insulin resistance, Macrophage activation
url http://www.sciencedirect.com/science/article/pii/S2212877818302321
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spelling doaj-fedf00fc7bf543b3ab7496c3a6c6834c2020-11-25T01:54:12ZengElsevierMolecular Metabolism2212-87782018-06-01124861Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intoleranceMark E. Pepin0Lindsey E. Padgett1Ruth E. McDowell2Ashley R. Burg3Manoja K. Brahma4Cassie Holleman5Teayoun Kim6David Crossman7Olaf Kutsch8Hubert M. Tse9Adam R. Wende10Kirk M. Habegger11Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USADivision of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USADivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Genetics, Heflin Center for Genomic Science, University of Alabama at Birmingham, Birmingham, AL, USADivision of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USADivision of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Department of Pathology – Division of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Department of Medicine – Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.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. Keywords: Antiretroviral therapy, Obesity, Glucose intolerance, Adipose tissue inflammation, Insulin resistance, Macrophage activationhttp://www.sciencedirect.com/science/article/pii/S2212877818302321