The Role of Hydrogen Sulfide in Adipose Tissue Function and Angiogenesis

一氧化氮(NO)和硫化氢(H2S)等气体信号分子(气体递质)的生物利用度降低被认为是肥胖相关代谢性血管疾病的病理联系的现象。由于肥胖，小鼠和人类的血浆硫化氢水平都会降低。硫化氢的血管活性和细胞保护作用依赖于内皮型一氧化氮合酶(ENOS)产生的NO。NO是脂解、脂肪生成、血管生成和线粒体生物能量学的调节因子。我们将检验这一假设，即硫化氢是脂肪生成和血管生成的正向调节因子。具体目标1将通过使用胱硫醚-y-裂解酶(CSE)基因敲除小鼠模型来测试全身产生硫化氢的重要性。利用这一模型，我们将确定雄性和雌性CSE-KO小鼠在肥胖条件下(高脂肪饮食)和低脂肪饮食下的代谢表型。我们将使用稳定的同位素完成广泛的代谢表型，以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，我们将灌流带有和不带有一氧化氮合酶抑制剂(L-NAME)的一氧化氮自旋捕捉器(MGd-Fe2+)，以确定CSE的丢失是否改变了脂解和血流。我们将使用一种新的体外血管萌发试验来确定CSE在脂肪组织中的功能不依赖于血管生成。这项建议将通过利用Pennington Biomedical的现有资源，提供有关脂肪组织中硫化氢功能的新数据。

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.