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Implications of Obstructive Sleep Apnea for Fat Metabolism

Implications of Obstructive Sleep Apnea for Fat Metabolism
阻塞性睡眠呼吸暂停对脂肪代谢的影响
批准号:
10330845
负责人:
Naresh M Punjabi
金额:
$72.06万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-20 至 2023-06-30

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中文摘要
翻译
摘要 未经治疗的阻塞性睡眠呼吸暂停(OSA)是几种心脏代谢并发症的先兆,包括 高血压、胰岛素抵抗、糖耐量异常和2型糖尿病。尽管取得了进步 在确定阻塞性睡眠呼吸暂停综合征和代谢功能障碍之间的独立联系方面取得了进展 解释这种联系的机制仍然难以捉摸。众所周知,间歇性低氧血症 而反复唤醒是阻塞性睡眠呼吸暂停的两个病理特征,可以激活交感神经系统, 增加氧化应激,加剧全身炎症。我们的初步数据显示, 脂肪代谢也可能在阻塞性睡眠呼吸暂停综合征和脑损伤之间的因果链条中发挥重要作用。 葡萄糖动态平衡。因此,这项建议的首要目标是描述脂肪的像差。 阻塞性睡眠呼吸暂停综合征的新陈代谢。为了实现这一目标,我们将采用非常独特的组合 代谢表型和确定脂肪代谢、骨骼和脂肪的可能作用的方法 组织酶活性和Toll样受体(TLR)信号是阻塞性睡眠呼吸暂停综合征代谢功能障碍的中介。 此外,我们将检查几种关键的骨骼肌酶的活性是否与-氧化有关 如酰基辅酶A合成酶、肉碱棕榈酰基转移酶-1、-羟基辅酶A 阻塞性睡眠呼吸暂停综合征患者体内的脱氢酶(β-HAD)和柠檬酸合成酶(CS)均发生改变。最后,我们建议研究 OSA是否通过降低脂蛋白脂肪酶活性来干扰甘油三酯的细胞外水解 (LPL),它调节各种组织中FFA的供应,无论是储存还是氧化。以下两个具体内容 提出了目标。目标1:评估与年龄、性别、种族和肥胖无关的OSA严重程度是否 与以下变化有关:(1)全身脂肪分解和游离脂肪酸(FFA)氧化;(2)皮下 脂肪组织脂解;(3)骨骼肌酶(ACEs、Cpt-1、-HAD和CS)和TLR2/TLR4的活性 (4)骨骼肌和脂肪组织中LPL活性。目标2:确定治疗是否 阻塞性睡眠呼吸暂停伴气道正压(PAP)治疗将对以下方面产生有益的影响:(1)全身脂肪分解和 FFA氧化;(2)皮下脂肪组织脂肪分解;(3)骨骼肌酶活性(ACS、CPT-1、 -HAD、CS)和TLR2/TLR4的表达;(4)骨骼肌和脂肪组织中LPL的活性。 完成这些目标将增加对OSA如何改变血糖和脂肪的迫切需要的机械性见解 新陈代谢,并有助于开启新的治疗策略(即,中断脂肪分解),可能会减少 OSA造成的代谢负担,特别是那些无法使用PAP疗法的人。
英文摘要
ABSTRACT Untreated obstructive sleep apnea (OSA) is a precursor for several cardio-metabolic complications including hypertension, insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Despite advancements made in identifying an independent association between OSA and metabolic dysfunction, underlying mechanisms that explicate the association remain elusive. It is well established that intermittent hypoxemia and recurrent arousals, the two pathognomonic features of OSA, can activate the sympathetic nervous system, increase oxidative stress, and heighten systemic inflammation. Our preliminary data indicate that alterations in fat metabolism may also have a fundamental role in the causal chain between OSA and impairments in glucose homeostasis. Thus, the overarching objective of this proposal is to characterize aberrations in fat metabolism in OSA. To accomplish this objective, we will employ a combination of exceptionally unique methods for metabolic phenotyping and determine the putative roles of fat metabolism, skeletal and adipose tissue enzymatic activity, and toll-like receptor (TLR) signaling as mediators of metabolic dysfunction in OSA. Moreover, we will examine whether activity of several key skeletal muscle enzymes involved in -oxidation such as acyl-CoA synthase (ACS), carnitine palmitoyltransferase-1 (CPT-1), -hydroxyacyl-CoA dehydrogenase (β-HAD) and citrate synthase (CS) are altered in OSA. Finally, we propose to examine whether OSA interferes with extracellular triglyceride hydrolysis by decreasing the activity of lipoprotein lipase (LPL), which regulates FFA supply in various tissues for either storage or oxidation. The following two specific aims are proposed. Aim 1: To assess whether, independent of age, sex, race, and obesity, OSA severity is associated with alterations in: (1) whole body lipolysis and free fatty acid (FFA) oxidation; (2) subcutaneous adipose tissue lipolysis; (3) activity of skeletal muscle enzymes (ACS, CPT-1, -HAD, and CS) and TLR2/TLR4 expression; and (4) LPL activity in skeletal muscle and adipose tissue. Aim 2: To determine whether treatment of OSA with positive airway pressure (PAP) therapy will have salutary effects on: (1) whole body lipolysis and FFA oxidation; (2) subcutaneous adipose tissue lipolysis; (3) activity of skeletal muscle enzymes (ACS, CPT-1, -HAD, and CS) and TLR2/TLR4 expression; and (4) LPL activity in skeletal muscle and adipose tissue. Completion of these aims will add much needed mechanistic insight on how OSA alters glucose and fat metabolism and help open new therapeutic strategies (i.e., interruption of lipolysis) that could curtail the metabolic burden imposed by OSA particularly in those that are unable to use PAP therapy.
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会议论文
Promoting Under-Representative Minorities in Pulmonary and Sleep Research (PURPOSE)
Implications of Obstructive Sleep Apnea for Fat Metabolism
A Multilevel Intervention to Reduce Disparities in Obstructive Sleep Apnea and Related Cardiometabolic Outcomes
A Multilevel Intervention to Reduce Disparities in Obstructive Sleep Apnea and Related Cardiometabolic Outcomes
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