1. Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
- Author
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David K. Crossman, Manoja K. Brahma, Lindsey E. Padgett, Hubert M. Tse, Ruth E. McDowell, Cassie Holleman, Teayoun Kim, Adam R. Wende, Ashley R. Burg, Kirk M. Habegger, Mark E Pepin, and Olaf Kutsch
- 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 - 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., Graphical abstract Image 1, 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.
- Published
- 2018