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: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333359
• 关键词: Abdomen; Adipocytes; Adipose tissue; Anatomy; Aspirate substance; Biogenesis; Biology; Body Composition; Body Weight decreased; Body measure procedure; Brown Fat; Cardiovascular system; Cells; Chronic; Clinical Trials; Consumption; Data; Energy Metabolism; Enzyme Inhibition; Evaluation; Exhibits; Experimental Models; Exposure to; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Genes; Genetic Transcription; Health; Human; Image; Imaging Techniques; Intervention; Link; Lipids; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Mitochondria; Mus; Natriuretic Peptides; Obesity; Participant; Perfusion; Periodicity; Pharmaceutical Preparations; Pharmacology; Phenotype; Physical activity; Physiological; Placebos; Protocols documentation; Public Health; Publishing; Randomized; Research Personnel; Resistance; Rest; Sampling; Second Messenger Systems; Signal Transduction; Stimulus; Techniques; Technology; Temperature; Thermogenesis; Thermometry; Time; Tissue Sample; Tissues; Transgenic Mice; Weight Gain; Wild Type Mouse; adult obesity; base; cardiovascular risk factor; diabetes risk; doubly-labeled water; energy balance; experimental study; guanylate; imaging biomarker; improved; inhibitor; insulin sensitivity; lifestyle intervention; lipid metabolism; metabolic rate; molecular marker; non-invasive imaging; obese person; phosphoric diester hydrolase; primary endpoint; response; secondary endpoint; spectroscopic imaging; subcutaneous; tadalafil

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.

抽象的 肥胖的特征是过量的白脂肪组织（WAT），其代谢活性低。最近的 研究表明，可以将WAT中的细胞驱动到代谢活性的棕色脂肪表型 （称为“存在”），有时与体重减轻和改善的胰岛素敏感性有关。 刺激成为WAT的药理学疗法和棕色脂肪组织的激活（BAT）可能 减少肥胖症中心血管和糖尿病风险。环状鸟苷酸一磷酸（CGMP）信号传导可能 积极影响脂肪组织代谢。 CGMP是Natrieteric的第二个使者 在肥胖症中减少的肽。暴露于外源性纳特里奶酪的野生型小鼠有 在WAT和BAT中与棕色脂肪细胞相关基因的表达增加，为成为的证据提供了证据 WAT和蝙蝠的激活。增强人类CGMP信号传导的安全且廉价的策略是 抑制与其分解，磷酸二酯酶5A型酶（PDE5）的抑制作用。有关影响的数据 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 缺乏一种非侵入性方法来检测活性蝙蝠和成为WAT的方法。我们已经开发了 发布了一种磁共振成像技术，以量化WAT中的脂质代谢的全部 和使用脂肪信号分数（FSF）的蝙蝠。在初步数据中，我们表明1）冷暴露（CGMP刺激） 2）慢性PDE5暴露可改善肥胖成年人的胰岛素敏感性，以及 3）用PDE5抑制剂治疗的小鼠暴露于增加能量消耗和对体重增加的耐药性。我们 假设肥胖的成年人的PDE5抑制作用将导致蝙蝠的活化和激活。我们将 执行非侵入性成像和皮下脂肪吸气，以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。我们将将参与者随机到达拉非（20mg/day）或 安慰剂3个月。端点将在室温和冷曝光方案后测量， 这将使我们能够通过PDE5抑制“ Primes”来确定CGMP音调长期增加 蝙蝠和WAT在纳地钠肽刺激的情况下激活。 AIM 1将检查 PDE5对脂肪代谢的抑制。我们将将100个肥胖个体随机到达拉非或安慰剂3 月份。主要终点是室温下的WAT FSF。 AIM 2将检查PDE5的效果 对皮下WAT基因表达的抑制。主要终点将是wat ucp1的变化 表达3个月。次要目的将链接来自目标1和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。这个目标的重要性 是在人类中首次建立成像与脂肪分子标记之间的关系 代谢。重新利用PDE5抑制剂可能是生活方式干预措施的重要辅助 肥胖个体的反心血管和糖尿病风险。