Division 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, USA.
Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Mol Metab. 2018 Jun;12:48-61. doi: 10.1016/j.molmet.2018.04.006. Epub 2018 Apr 20.
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.
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.
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.
The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.
艾滋病治疗方面的突破，尤其是联合抗逆转录病毒疗法（ART），极大地降低了艾滋病相关死亡率。然而，ART 的应用增加了非艾滋病定义性疾病的风险，包括肥胖、糖尿病和心血管疾病，统称为代谢综合征。初步报告表明，与 ART 相关的代谢综合征风险与社会经济地位相关，这是一个多方面的发现，包括收入、种族、教育和饮食。因此，由于病毒感染、ART 和许多环境因素之间的复杂相互作用，确定因果关系极具挑战性。
在目前的研究中，我们使用了一种小鼠模型，专门研究了影响能量平衡和葡萄糖代谢的 ART 和饮食之间的相互作用。先前的研究表明，高脂肪饮食会引起持续的低度全身和脂肪组织炎症，通过脂肪组织浸润的巨噬细胞导致胰岛素抵抗和代谢失调。本研究检验了 ART 增强高脂肪饮食（HFD）的炎症作用的假设。在 HFD 或含有 ART 或载体的标准饲料上的 C57Bl/6J 小鼠接受了功能代谢测试、附睾白色脂肪组织（eWAT）的 RNA 测序和 eWAT 浸润巨噬细胞的基于阵列的激酶组分析。
接受 HFD 治疗的 ART 小鼠表现出脂肪量增加、葡萄糖耐量受损和胰岛素抵抗加剧。基因集富集和激酶组阵列分析显示出促炎转录特征，描绘了粒细胞迁移和激活。
本研究揭示了 HFD-ART 相互作用，增加了炎症转录途径，并损害了葡萄糖代谢、能量平衡和代谢功能障碍。
