Nitrite and Hypoxia Increase Mitochondrial Biogenesis and Insulin Sensitivity

亚硝酸盐和缺氧增加线粒体生物发生和胰岛素敏感性

• 批准号: 9008066
• 负责人: CHRISTOPHER P O'DONNELL
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008066
• 关键词: Accounting; Altitude; Animals; Attenuated; Behavioral; Bioavailable; Biogenesis; Biological Availability; Blood Circulation; Blood Vessels; Blood flow; Chronic; Control Groups; Data; Diabetes Mellitus; Diet; Endocrine; Endothelium; Epidemic; Exhibits; Exposure to; Functional disorder; Genetic; Glucose; Health; Health Benefit; Human; Hypoxia; In Vitro; Insulin; Insulin Resistance; Intervention; Knock-out; Literature; Mediating; Mediterranean Diet; Metabolic; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obstructive Sleep Apnea; Oxidative Phosphorylation; Pathway interactions; Phosphorylation; Production; Public Health; Publishing; Rodent; Role; Seminal; Societies; Soluble Guanylate Cyclase; Source; Stimulus; Stress; Testing; Time; Tissues; glucose uptake; hypoxia inducible factor 1; improved; innovation; insight; insulin sensitivity; interest; novel therapeutics; oxidation; response; treatment strategy

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.

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。不断需要设计新的疗法，包括提供长期疗效的行为和药理干预。我们最近意外地发现，对连续缺氧（CH;即模拟海拔暴露）的慢性适应可以增加瘦小鼠的胰岛素敏感性。此外，即使暴露于轻度夜间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，增加循环亚硝酸盐，缺氧期间生物活性一氧化氮（NO）的主要来源，可能有助于CH的代谢益处。我们的数据表明，缺氧和亚硝酸盐管理相结合是一种有效的刺激，用于上调缺氧诱导因子-1（HIF-1），增加线粒体生物合成，并减少肌肉中的氧化磷酸化过载。我们将研究在肌层水平上增加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途径在介导增加胰岛素敏感性和肌肉葡萄糖摄取响应缺氧暴露和亚硝酸盐管理的贡献。我们的总体假设是，长期暴露于轻度夜间CH和外源性亚硝酸盐给药通过激活HIF-1？和增加NO的生物利用度增加肌肉葡萄糖摄取。将在遗传性和饮食诱导的肥胖小鼠中测试以下四个特定目的。目的1：探讨慢性低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 肥胖小鼠在常氧和低氧条件下的胰岛素敏感性，和（B）评估增加的血流量相对于肌肉特异性作用对增加胰岛素敏感性和肌肉葡萄糖摄取的作用。目标三：确定HIF-1在慢性低氧暴露和亚硝酸盐给药介导肌肉葡萄糖/胰岛素递送和肌肉葡萄糖摄取增加中的作用。目标4：确定慢性低氧暴露和亚硝酸盐给药下生物可利用的NO通过NO-sGC途径增加肌肉葡萄糖摄取的机制。我们的研究不仅将为与肥胖和胰岛素抵抗相关的代谢功能障碍提供新的机制见解，而且还将研究两种尚未经过测试的相互作用的新疗法改善胰岛素敏感性的潜力。

项目成果

Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance.

无机亚硝酸盐可改善代谢综合征的各个组成部分，与肥胖和胰岛素抵抗小鼠模型中的体重变化无关。

• DOI: 10.1113/jp270386
• 发表时间: 2015
• 期刊: The Journal of physiology
• 作者: Singamsetty,Srikanth;Watanabe,Yoshio;Guo,Lanping;Corey,Catherine;Wang,Yinna;Tejero,Jesus;McVerry,BryanJ;Gladwin,MarkT;Shiva,Sruti;O'Donnell,ChristopherP
• 通讯作者: O'Donnell,ChristopherP