The Role of Hydrogen Sulfide in Adipose Tissue Function and Angiogenesis

硫化氢在脂肪组织功能和血管生成中的作用

• 批准号: 10569520
• 负责人: Timothy Allerton
• 金额: $ 22.2万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569520
• 关键词: Adipose tissue; Bioenergetics; Biological Assay; Biological Availability; Blood Vessels; Blood flow; Cystathionine; Cytoprotection; Data; Disease; Energy Metabolism; Fat-Restricted Diet; Female; High Fat Diet; Human; Hydrogen Sulfide; Knockout Mice; Link; Lipolysis; Lyase; Metabolic; Microdialysis; Mitochondria; Modeling; Mus; NG-Nitroarginine Methyl Ester; NOS3 gene; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Obesity; Pathology; Plasma; Production; Resources; Role; Signaling Molecule; Spin Trapping; System; Testing; Vascular Diseases; Wild Type Mouse; angiogenesis; glucose metabolism; lipid biosynthesis; male; metabolic phenotype; mouse model; novel; obesogenic; oxidation; stable isotope

The reduced bioavailability of gaseous signaling molecules (gasotransmitters) such as nitric oxide (NO) and hydrogen sulfide (H2S) is considered phenomenon linking the pathology of obesity-associated metabolic-vascular disease. Plasma H2S is reduced as a consequence of obesity in mice and humans. The vasoactive and cytoprotective actions of H2S are mutually dependent on endothelial nitric oxide synthase (eNOS) production of NO. NO is a regulator of lipolysis, adipogenesis, angiogenesis and mitochondrial bioenergetics. We will test the hypothesis that H2S is a positive regulator of adipogenesis and angiogenesis. Specific Aim 1 will tests the importance of whole body H2S production by using the cystathionine-y-lyase (CSE) knockout mouse model. Using this model, we will determine the metabolic phenotype of male and female CSE-KO mice under obesogenic conditions (high fat diet) compared to a low fat diet. We will complete extensive metabolic phenotyping using stable isotope to assess dynamic glucose metabolism and adipogenesis. We will also use the metabolic cage system in the Pennington Metabolic Phenotyping core to determine alterations in energy expenditure and substrate oxidation between CSE KO and wild type mice. In aim 2 we will investigate the effect of obesity on adipose tissue microvascular function in CSE KO mice. Using a novel microdialysis approach we will perfustate a nitric oxide spin trap (MGD-Fe2+) with and without a nitric oxide synthase inhibitor (L-NAME) to determine if loss of CSE alters lipolysis and blood flow. We will use a novel ex vivo vessel sprouting assay to determine CSE function in adipose tissue angiogenesis is NO-dependent. This proposal will provide novel data on the function of H2S in the adipose tissue by leveraging the resources available at Pennington Biomedical.

气体信号分子（气体递质）如一氧化氮（NO）和硫化氢（H2S）的生物利用度降低被认为是与肥胖相关的代谢血管疾病的病理学相关的现象。在小鼠和人类中，由于肥胖，血浆H2S减少。H2S的血管活性和细胞保护作用相互依赖于NO的内皮型一氧化氮合酶（eNOS）产生。NO是脂解、脂肪生成、血管生成和线粒体生物能量学的调节剂。我们将检验H2S是脂肪生成和血管生成的正调节剂的假设。具体目标1将通过使用胱硫醚-γ-裂解酶（CSE）敲除小鼠模型来测试全身H2S产生的重要性。使用该模型，我们将确定雄性和雌性CSE-KO小鼠在致肥胖条件下（高脂肪饮食）与低脂饮食相比的代谢表型。我们将使用稳定同位素完成广泛的代谢表型分析，以评估动态葡萄糖代谢和脂肪生成。我们还将在彭宁顿代谢表型核心中使用代谢笼系统，以确定CSE KO和野生型小鼠之间能量消耗和底物氧化的变化。在目标2中，我们将研究肥胖对CSE KO小鼠脂肪组织微血管功能的影响。使用一种新的微透析方法，我们将perfustate一氧化氮自旋捕集器（MGD-Fe 2+）与和不与一氧化氮合酶抑制剂（L-NAME），以确定如果损失的CSE改变脂解和血流。我们将使用一种新的离体血管发芽试验来确定CSE在脂肪组织血管生成中的功能是NO依赖性的。该提案将通过利用彭宁顿生物医学的可用资源，提供有关H2S在脂肪组织中的功能的新数据。