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

摘要 HIV和抗逆转录病毒疗法(ART)与脂肪组织(AT)功能障碍和 全身代谢改变，包括腹内脂肪堆积，脂肪肝， 血脂异常和胰岛素抵抗。使用常规药物和药物治疗这些缺陷 生活方式干预的效果微乎其微。病毒因素和ART导致了 艾滋病毒携带者这些疾病状态的复杂病理生理学。尽管如此， 将病毒因子和ART与AT和肝脏代谢缺陷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了HIV病毒的附件 VPR蛋白足以引起HIV相关代谢的所有主要表现 疾病。Vpr小鼠也有高水平的FGF21和皮下AT增加 生热作用。目前的提案旨在建立两国之间的机械联系 FGF21水平升高，白色AT产热，以及观察到的代谢异常 VPR小鼠和PLWH。我们的中心假设是VPR的表达改变了新陈代谢的影响 FGF21改变血管紧张素转换酶和肝功能，诱导不适应性皮下褐变 怀特看着。我们将通过实现以下具体目标来检验这一假设：1)确定 VPR暴露如何影响小鼠的白色AT产热；2)演示FGF21如何形成 Vpr小鼠的代谢异常；3)成纤维细胞生长因子21与S内分泌的关系 脂糖代谢和皮下白质AT功能的作用和缺陷 关于压抑艺术的PLWH。我们的研究计划将提供对 人类免疫缺陷病毒相关代谢性疾病与成纤维细胞生长因子21的生理、分子关系 生热机制、AT生理学和免疫学。该项目将揭示 VPR小鼠模型中独特代谢缺陷的机制概括了PLWH中的机制， 阐明成纤维细胞生长因子21‘S的内分泌功能对艾滋病毒相关代谢的影响 PLWH在ART上的异常。最终，这项翻译工作将确定 HIV特异性代谢改变，并可能确定可利用的治疗靶点 将PLWH中代谢性疾病的长期临床负担降至最低。

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.