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: 10557112
• 负责人: Evan L Brittain
• 金额: $ 69.61万
• 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/10557112
• 关键词: Abdomen; Adipocytes; Adipose tissue; Anatomy; Biogenesis; Biology; Body Composition; Body Weight decreased; Body measure procedure; Brown Fat; Cardiovascular system; Cells; Chronic; Clinical Trials; Data; Energy Metabolism; Energy consumption; Enzyme Inhibition; Evaluation; Exhibits; Experimental Models; Exposure to; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Genes; Genetic Transcription; Health; Human; Imaging Techniques; Intervention; Link; Lipids; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Mitochondria; Mus; Natriuretic Peptides; Obesity; Participant; Perfusion; Periodicity; Pharmaceutical Preparations; Phenotype; Physical activity; Physiological; Placebos; Protocols documentation; Public Health; Publishing; Randomized; Research Personnel; Resistance; Rest; Sampling; Second Messenger Systems; Signal Transduction; Spectrum Analysis; Stimulus; Techniques; Technology; Temperature; Thermogenesis; Thermometry; Time; Tissue Sample; Tissues; Transgenic Mice; Weight Gain; Wild Type Mouse; adipose imaging; adult obesity; aspirate; 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; pharmacologic; phosphoric diester hydrolase; primary endpoint; response; secondary endpoint; 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.

摘要 肥胖症的特征在于过量的白色脂肪组织（WAT），其具有低代谢活性。最近 研究表明，WAT中的细胞可以被驱动向代谢活性的棕色脂肪表型， （称为“beiging”），其与体重减轻和改善的胰岛素敏感性有因果关系。 刺激WAT的褐变和棕色脂肪组织（BAT）的活化的药物疗法可以 降低肥胖者的心血管和糖尿病风险。环鸟苷酸一磷酸（cGMP）信号传导可能 积极影响脂肪组织代谢。cGMP是利钠肽的第二信使 肽，这是减少肥胖。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，为棕色脂肪细胞相关基因的表达提供了证据。 WAT和BAT的激活。增强人体cGMP信号传导的安全且廉价的策略是 抑制参与其分解的酶，磷酸二酯酶5A型（PDE 5）。影响数据 PDE 5对人体WAT和BAT功能的抑制作用有限。人类研究的一个障碍是 缺乏一种非侵入性的方法来检测激活的BAT和WAT的Beiging。我们已经开发并 发表了一项磁共振成像技术，以量化WAT中脂质代谢的全谱 和使用脂肪信号分数（FSF）的BAT。在初步数据中，我们表明：1）冷暴露（cGMP刺激） 导致人类WAT的增加，2）慢性PDE 5暴露改善肥胖成年人的胰岛素敏感性， 3)用PDE 5抑制剂处理的小鼠表现出增加的能量消耗和对体重增加的抵抗力。我们 假设肥胖成人中PDE 5抑制将导致WAT的减弱和BAT的激活。我们将 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。我们将受试者随机分配至他达拉非（20 mg/天）或 安慰剂3个月。将在室温下和冷暴露方案后测量终点， 这将使我们能够确定通过PDE 5抑制“引发”cGMP张力的慢性增加是否 BAT和WAT用于在利钠肽刺激设置中激活。目标1将研究 PDE 5对脂肪代谢的抑制。我们将100名肥胖患者随机分为他达拉非组和安慰剂组， 个月主要终点是室温下的WAT FSF。目标2将检查PDE 5的作用 抑制皮下WAT基因表达。主要终点将是WAT UCP 1的变化 3个月的表达。次要目标将链接目标1和目标2的数据，以检查目标1和目标2之间的关联。 PDE 5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成像和脂肪分子标记之间的关系， 新陈代谢. PDE 5抑制剂的再利用可能是生活方式干预的重要辅助手段， 对抗肥胖者的心血管和糖尿病风险。