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Effect of PDE5 Inhibition on Adipose Metabolism in Humans

Effect of PDE5 Inhibition on Adipose Metabolism in Humans
PDE5 抑制对人体脂肪代谢的影响
批准号:
10333359
负责人:
Evan L Brittain
金额:
$69.6万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-02-01 至 2026-01-31

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中文摘要
翻译
摘要 肥胖的特征是白色脂肪组织(WAT)过多,代谢活动较低。近期 研究表明,WAT中的细胞可以被驱使向代谢活跃的棕色脂肪表型发展 (称为“褐变”),这与减肥和改善胰岛素敏感性有因果关系。 刺激褐变和棕色脂肪组织(BAT)激活的药物疗法可能 降低肥胖引起的心血管疾病和糖尿病风险。环磷酸鸟苷(CGMP)信号转导可以 对脂肪组织代谢有积极影响。CGMP是利钠药的第二信使 在肥胖症中减少的多肽。暴露于外源性利钠肽的野生型小鼠 棕色脂肪细胞相关基因在WAT和BAT中的表达增加,为褐变提供了证据 WAT和BAT的激活。一种安全而廉价的增强人类cGMP信号的策略是 抑制与其分解有关的一种酶,磷酸二酯酶5A型(PDE5)。关于以下影响的数据 PDE5对人类的WAT和BAT功能的抑制是有限的。人类研究的一个障碍是 缺乏一种非侵入性的方法来同时检测激活的蝙蝠和褐变的Wat。我们已经开发出了 发布了一项磁共振成像技术,以量化水中脂类代谢的全谱 以及使用脂肪信号分数(FSF)的BAT。在初步数据中,我们发现:1)冷暴露(cGMP刺激) 2)长期接触PDE5可改善肥胖成年人的胰岛素敏感性, 3)用PDE5抑制剂治疗的小鼠能量消耗增加,对体重增加有抵抗力。我们 假设在肥胖的成年人中抑制PDE5会导致WAT的褐变和BAT的激活。我们会 进行非侵入性成像和皮下脂肪抽吸,将脂肪成像和基因的变化联系起来 首次在同一解剖部位表达。我们将随机给受试者服用他达拉非(20 mg/天)或 安慰剂3个月。将在室温下并在冷暴露方案之后测量终点, 这将使我们能够确定cGMP音调的慢性增加是否通过抑制PDE5的“质数” BAT和WAT用于在设置利钠肽刺激时激活。目标1将考察以下因素的影响 PDE5抑制脂肪代谢。我们将随机选择100名肥胖者服用他达拉非或安慰剂,疗程3年。 月份。主要终点是室温下的Wat FSF。目标2将检查PDE5的影响 抑制皮下Wat基因表达。主端点将在WAT UCP1中更改 在3个月时表现出来。次要目标将链接来自目标1和目标2的数据,以检查 PDE5抑制和冷暴露后FSF和WAT基因表达的变化。这一目标的重要性 是首次在人类中建立脂肪的成像和分子标记之间的关系 新陈代谢。重新调整PDE5抑制剂的用途可能是生活方式干预的重要辅助手段,以努力 降低肥胖人群的心血管和糖尿病风险。
英文摘要
ABSTRACT Obesity is characterized by an excess of white adipose tissue (WAT), which has low metabolic activity. Recent studies demonstrate that cells in WAT can be driven toward a metabolically active brown adipose phenotype (termed “beiging”), which is causally associated with weight loss and improved insulin sensitivity. Pharmacologic therapies to stimulate beiging of WAT and activation of brown adipose tissue (BAT) may reduce cardiovascular and diabetes risk in obesity. Cyclic guanylate monophosphate (cGMP) signaling may positively influence adipose tissue metabolism. cGMP serves as the second messenger for the natriuretic peptides, which are reduced in obesity. Wild type mice exposed to exogenous natriuretic peptide have increased expression of brown adipocyte-associated genes in WAT and BAT, providing evidence for beiging of WAT and activation of BAT. A safe and inexpensive strategy to enhance cGMP signaling in humans is inhibition of an enzyme involved in its breakdown, phosphodiesterase type 5A (PDE5). Data on the effects of PDE5 inhibition on WAT and BAT function in humans are limited. One barrier to human studies has been the lack of a non-invasive method to detect both activated BAT and beiging of WAT. We have developed and published a magnetic resonance imaging technique to quantify the full spectrum of lipid metabolism in WAT and BAT using fat signal fraction (FSF). In preliminary data, we show that 1) cold exposure (a cGMP stimulus) causes beiging of WAT in humans, 2) chronic PDE5 exposure improves insulin sensitivity in obese adults and, 3) mice treated with PDE5 inhibitors exhibit increased energy expenditure and resistance to weight gain. We hypothesize that PDE5 inhibition in obese adults will result in beiging of WAT and activation of BAT. We will perform non-invasive imaging and subcutaneous fat aspiration to link changes in adipose imaging and gene expression at the same anatomic site for the first time. We will randomize participants to tadalafil (20mg/day) or placebo for 3 months. Endpoints will be measured at room temperature and after a cold exposure protocol, which will allow us to determine whether a chronic increase in cGMP tone through PDE5 inhibition “primes” BAT and WAT for activation in the setting of a natriuretic peptide stimulus. Aim 1 will examine the effect of PDE5 inhibition on adipose metabolism. We will randomize 100 obese individuals to tadalafil or placebo for 3 months. The primary endpoint is WAT FSF at room temperature. Aim 2 will examine the effect of PDE5 inhibition on subcutaneous WAT gene expression. The primary endpoint will be change in WAT UCP1 expression at 3 months. A secondary aim will link data from Aims 1 and 2 to examine the association between change in FSF and WAT gene expression after PDE5 inhibition and cold exposure. The importance of this aim is to establish for the first time in humans the relationship between imaging and molecular markers of adipose metabolism. Repurposing PDE5 inhibitors could be an important adjunct to lifestyle interventions in an effort to counter cardiovascular and diabetes risk in obese individuals.
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国内基金
海外基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制