Metabolic impact of FGF-21 in adipose tissue and liver of PLWH

摘要 HIV和抗逆转录病毒治疗（ART）与脂肪组织（AT）功能障碍有关， 全身代谢改变，包括腹内脂肪蓄积、脂肪肝疾病， 血脂异常和胰岛素抵抗。使用常规药物治疗这些缺陷， 生活方式干预的效果微乎其微。病毒因素和ART有助于 这些疾病的复杂病理生理状态的人与艾滋病毒（PLWH）。不过 将病毒因子和ART与AT缺陷和肝脏代谢联系起来的机制仍然存在 不完全理解。我们已经在小鼠模型中证明， 蛋白Vpr足以引起HIV相关代谢的所有主要表现， 疾病Vpr小鼠还具有高水平的FGF 21和增加的皮下AT 产热作用目前的建议旨在建立机械联系， 增加的FGF 21水平，白色AT产热，以及观察到的 Vpr小鼠和PLWH.我们的中心假设是Vpr表达改变了代谢效应， 改变AT和肝功能，并诱导皮下组织适应不良的布朗宁。 白色AT.我们将通过实现以下具体目标来测试这一假设：1）确定 Vpr暴露如何影响小鼠中的白色AT产热; 2）证明FGF 21如何形成 Vpr小鼠的代谢异常; 3）建立FGF 21与内分泌的关系 脂糖代谢和皮下白色AT功能的作用和缺陷 我们的研究计划将提供详细的解剖， HIV相关代谢疾病与FGF 21生理、分子 产热机制和AT生理学以及免疫学。该项目将揭示 Vpr小鼠模型中独特的代谢缺陷机制概括了PLWH中的机制， 并阐明FGF 21的内分泌功能如何促进HIV相关的代谢， 最终，这项翻译工作将确定PLWH的机制， HIV特异性代谢改变，并可能确定可用于治疗的治疗靶点， 最大限度地减少PLWH中代谢性疾病的长期临床负担。

ABSTRACT HIV and antiretroviral therapy (ART) are associated with adipose tissue (AT) dysfunction and systemic metabolic alterations, including intra-abdominal fat accumulation, fatty liver disease, dyslipidemia, and insulin resistance. Treatment of these defects using conventional drugs and lifestyle interventions has been minimally effective. Viral factors and ART contribute to the complex pathophysiology of these disease states in persons living with HIV (PLWH). Still, the mechanisms that link viral factors and ART to defective AT and hepatic metabolism remain incompletely understood. We have demonstrated in mouse models that the HIV accessory protein Vpr is sufficient to cause all the cardinal manifestations of HIV-associated metabolic disease. The Vpr mice also have high levels of FGF21 and increased subcutaneous AT thermogenesis. The current proposal aims to establish mechanistic connections between increased FGF21 levels, white AT thermogenesis, and the observed metabolic abnormalities in Vpr mice and PLWH. Our central hypothesis is that Vpr expression alters the metabolic effects of FGF21, altering AT and hepatic function and inducing maladaptive browning of subcutaneous white AT. We will test this hypothesis by achieving the following Specific Aims: 1) Determine how Vpr exposure affects white AT thermogenesis in mice; 2) Demonstrate how FGF21 shapes the metabolic abnormalities of Vpr mice; 3) Establish relationships between FGF21’s endocrine actions and defects of lipid and glucose metabolism and subcutaneous white AT function in PLWH on suppressive ART. Our research plan will provide detailed dissection of the relationships between HIV-associated metabolic disease and FGF21 physiology, molecular mechanisms of thermogenesis and AT physiology, and immunology. The project will reveal mechanisms of unique metabolic defects in Vpr mouse models that recapitulate those in PLWH, and elucidate how FGF21’s endocrine functions contribute to HIV-associated metabolic abnormalities in PLWH on ART. Ultimately, this translational work will identify mechanisms of HIV-specific metabolic alterations and may identify therapeutic targets that can be exploited to minimize the long-term clinical burden of metabolic disease in PLWH.