Effect of PDE5 Inhibition on Adipose Metabolism in Humans

PDE5 抑制对人体脂肪代谢的影响

基本信息

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
项目类别：
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

项目摘要

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.

抽象的肥胖的特征是白色脂肪组织（WAT）过多，其代谢活性较低。研究表明，WAT 中的细胞可以被驱动为代谢活跃的棕色脂肪表型（称为“米色”），它与体重减轻和胰岛素敏感性改善有因果关系。刺激 WAT 开始和棕色脂肪组织 (BAT) 激活的药物疗法可能环鸟苷酸单磷酸 (cGMP) 信号传导可能会降低肥胖者的心血管和糖尿病风险。积极影响脂肪组织代谢。cGMP 是利尿钠的第二信使。暴露于外源性利尿钠肽的野生型小鼠体内的肽含量减少。 WAT 和 BAT 中棕色脂肪细胞相关基因的表达增加，为 WAT 和 BAT 的激活是增强人类 cGMP 信号传导的安全且廉价的策略。抑制参与其分解的酶，5A 型磷酸二酯酶 (PDE5) 的影响数据。 PDE5 对人类 WAT 和 BAT 功能的抑制作用是有限的。缺乏一种非侵入性方法来检测激活的 BAT 和 WAT 的开始。发表了一种磁共振成像技术来量化 WAT 中脂质代谢的全谱和 BAT 使用脂肪信号分数 (FSF) 在初步数据中，我们表明 1) 冷暴露（cGMP 刺激）。导致人类变成 WAT，2) 长期接触 PDE5 可提高肥胖成人的胰岛素敏感性，并且， 3) 用 PDE5 抑制剂治疗的小鼠表现出能量消耗增加和体重增加抵抗力。我们将培养肥胖成人中 PDE5 抑制将导致 WAT 的开始和 BAT 的激活。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，我们将随机将参与者分配到他达拉非（20 毫克/天）或安慰剂 3 个月后，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是否通过 PDE5 抑制“启动”cGMP 音调的慢性增加在利钠肽刺激的情况下激活 BAT 和 WAT 的效果将检查。 PDE5 对脂肪代谢的抑制我们将 100 名肥胖个体随机分为 3 组，分别服用他达拉非或安慰剂。主要终点是室温下的 WAT FSF 目标 2 将检查 PDE5 的影响。皮下 WAT 基因表达的抑制主要终点是 WAT UCP1 的变化。第二个目标是将目标 1 和 2 的数据联系起来，以检查之间的关联。 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。是首次在人体中建立脂肪成像和分子标记之间的关系重新利用 PDE5 抑制剂可能是生活方式干预的重要辅助手段。降低肥胖者的心血管和糖尿病风险。