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Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
- Source :
- Molecular Metabolism, Molecular Metabolism, Vol 12, Iss, Pp 48-61 (2018)
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
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.<br />Graphical abstract Image 1<br />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.
- Subjects :
- 0301 basic medicine
eWAT, epididymal white adipose tissue
Adipose tissue
White adipose tissue
ATM, adipose tissue macrophage
Impaired glucose tolerance
ART, antiretroviral therapy
Mice
0302 clinical medicine
HFD, high fat diet
Adipose tissue inflammation
Cells, Cultured
PTK, protein tyrosine kinase
3. Good health
Antiretroviral therapy
HIV, human immunodeficiency virus
HOMA-IR, homeostatic model assessment of insulin resistance
Anti-Retroviral Agents
GTT, glucose tolerance test
Original Article
Granulocyte migration
medicine.medical_specialty
lcsh:Internal medicine
NAFLD, non-alcoholic fatty liver disease
Adipose Tissue, White
030209 endocrinology & metabolism
Carbohydrate metabolism
STK, serine/threonine kinase
Diet, High-Fat
03 medical and health sciences
Insulin resistance
ROS, reactive oxygen species
Diabetes mellitus
Internal medicine
Glucose Intolerance
medicine
Animals
Obesity
Macrophage activation
lcsh:RC31-1245
Molecular Biology
ITT, insulin tolerance test
NO, nitric oxide
business.industry
Macrophages
Cell Biology
DIO, diet-induced obesity
medicine.disease
AIDS, acquired immunodeficiency syndrome
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
NRTIs, nucleoside reverse-transcriptase inhibitors
Metabolic syndrome
business
Transcriptome
SD, standard chow diet
T2D, type-2 diabetes
Subjects
Details
- Language :
- English
- ISSN :
- 22128778
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Molecular Metabolism
- Accession number :
- edsair.doi.dedup.....4a0bd10bb64080729538a3b5135bb0ca