The Role of Hydrogen Sulfide in Adipose Tissue Function and Angiogenesis

点击翻译按钮获取中文摘要

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.