The Role of Hydrogen Sulfide in Adipose Tissue Function and Angiogenesis

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与肥胖相关代谢血管疾病的病理有关。小鼠和人类的肥胖导致血浆H2S减少。H2S的血管活性和细胞保护作用相互依赖于内皮一氧化氮合酶（eNOS）产生NO。一氧化氮是脂肪分解、脂肪生成、血管生成和线粒体生物能量学的调节剂。我们将验证H2S是脂肪生成和血管生成的积极调节因子的假设。特异性目标1将通过使用半胱硫氨酸裂解酶（CSE）敲除小鼠模型来测试全身H2S产生的重要性。使用该模型，我们将确定在致肥条件下（高脂肪饮食）与低脂肪饮食下雄性和雌性CSE-KO小鼠的代谢表型。我们将使用稳定同位素完成广泛的代谢表型来评估动态葡萄糖代谢和脂肪生成。我们还将使用Pennington代谢表型核心中的代谢笼系统来确定CSE KO和野生型小鼠之间能量消耗和底物氧化的变化。在目的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，我们将对一氧化氮自旋阱（MGD-Fe2+）进行灌注，加入和不加入一氧化氮合酶抑制剂（L-NAME），以确定CSE的丢失是否会改变脂肪分解和血流。我们将使用一种新的体外血管发芽试验来确定CSE在脂肪组织血管生成中的功能是否依赖于no。该提案将利用Pennington Biomedical的现有资源，提供关于H2S在脂肪组织中的功能的新数据。

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.