Nitrite and Hypoxia Increase Mitochondrial Biogenesis and Insulin Sensitivity

描述（由申请人提供）：肥胖、胰岛素抵抗和糖尿病是一个日益严重的公共卫生问题，在西方社会已达到流行病的程度。不断需要设计新的治疗方法，包括提供长期疗效的行为和药物干预。我们最近出乎意料地发现，慢性适应持续缺氧（CH，即模拟高原暴露）可以增加瘦小鼠的胰岛素敏感性。此外，即使夜间轻度缺氧也能改善肥胖小鼠的胰岛素敏感性。文献和我们自己的数据表明，缺氧时循环亚硝酸盐（生物活性一氧化氮（NO）的主要来源）的增加可能有助于CH的代谢益处。我们的数据表明，缺氧和亚硝酸盐联合给药可以有效刺激缺氧诱导因子-1 （HIF-1）的上调，增加线粒体生物发生，减少肌肉中氧化磷酸化过载。我们将在肌细胞水平上研究增加的肌肉血流量与直接代谢适应的相对作用。此外，我们将研究组成型no -可溶性鸟苷酸环化酶（sGC）途径与非sGC途径在缺氧暴露和亚硝酸盐处理下介导胰岛素敏感性和肌肉葡萄糖摄取增加中的作用。我们的总体假设是，慢性暴露于轻度夜间CH和外源性亚硝酸盐管理通过激活HIF-1¿和增加NO的生物利用度增加肌肉葡萄糖摄取。以下四种Specific Aims将在遗传和饮食引起的肥胖小鼠中进行测试。目的1：探讨慢性缺氧对肥胖小鼠胰岛素敏感性的影响。目的2:(a)确定慢性亚硝酸盐给药对

DESCRIPTION (provided by applicant): Obesity, insulin resistance and diabetes are a growing public health issue that has reached epidemic proportions in Western society. There is a constant need to devise new therapies, including behavioral and pharmacologic interventions that offer long-term efficacy. We have recently, and unexpectedly, found that chronic adaptation to continuous hypoxia (CH; i.e. simulating altitude exposure) can increase insulin sensitivity in lean mice. Moreover, even exposure to mild nocturnal hypoxia improves insulin sensitivity in obese mice. The literature and our own data suggest that increased circulating nitrite, the predominant source of bioactive nitric oxide (NO) during hypoxia, likely contributes to the metabolic benefits of CH. Our data show that combining hypoxia and nitrite administration is a potent stimulus for upregulating hypoxia inducible factor-1¿ (HIF-1¿), increasing mitochondrial biogenesis, and decreasing oxidative phosphorylation overload in muscle. We will examine the relative roles of increased blood flow to muscle versus direct metabolic adaptations at the level of the myoctye. Furthermore, we will examine the contribution of the constitutive NO-soluble guanylate cyclase (sGC) pathway versus non-sGC pathways in mediating increases in insulin sensitivity and muscle glucose uptake in response to hypoxic exposure and nitrite administration. Our overarching hypothesis is that chronic exposure to mild nocturnal CH and exogenous nitrite administration increases muscle glucose uptake through activation of HIF-1¿ and increased bioavailability of NO. The following four Specific Aims will be tested in mice with genetic and diet-induced obesity. Aim 1: To determine the effects of chronic hypoxia on insulin sensitivity in obese mice. Aim 2: To (a) determine the effects of chronic nitrite administration on insulin sensitivity under normoxic and hypoxic conditions in obese mice and (b) to assess the role of increased blood flow versus muscle-specific effects on increasing insulin sensitivity and muscle glucose uptake. Aim 3: To determine the role of HIF-1¿ in mediating increases in muscle glucose/insulin delivery and muscle glucose uptake with chronic hypoxic exposure and nitrite administration. Aim 4: To determine the mechanisms by which bioavailable NO increases muscle glucose uptake through NO-sGC pathways with chronic hypoxic exposure and nitrite administration. Our studies will not only provide new mechanistic insights into metabolic dysfunction associated with obesity and insulin resistance, but also examine the potential of two, as yet untested, interacting novel therapies for improving insulin sensitivity.