Elsevier

Molecular Metabolism

Volume 12, June 2018, Pages 48-61
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2018.04.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • Antiretroviral therapy (ART) exacerbates high-fat diet induced obesity and dysregulation of glucose homeostasis.

  • Transcriptomic and Kinomic analyses identify increased pro-inflammatory, adipose-tissue macrophages after ART-treatment.

  • ART and high-fat diet synergistically induce the G-protein coupled receptor, Gpr50, in white adipose tissue.

Abstract

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

Abbreviations

AIDS
acquired immunodeficiency syndrome
ART
antiretroviral therapy
ATM
adipose tissue macrophage
DIO
diet-induced obesity
eWAT
epididymal white adipose tissue
GTT
glucose tolerance test
SD
standard chow diet
HFD
high fat diet
HIV
human immunodeficiency virus
HOMA-IR
homeostatic model assessment of insulin resistance
ITT
insulin tolerance test
NAFLD
non-alcoholic fatty liver disease
NO
nitric oxide
NRTIs
nucleoside reverse-transcriptase inhibitors
PTK
protein tyrosine kinase
ROS
reactive oxygen species
STK
serine/threonine kinase
T2D
type-2 diabetes

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