Implications of Obstructive Sleep Apnea for Fat Metabolism

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前兆，包括 高血压、胰岛素抵抗、葡萄糖耐受不良和2型糖尿病。尽管取得了进步 在确定OSA和代谢功能障碍之间的独立关联时， 解释这种关联的机制仍然难以捉摸。众所周知，间歇性低氧血症 和反复觉醒，OSA的两个特征，可以激活交感神经系统， 增加氧化应激和提高全身炎症。我们的初步数据表明， 脂肪代谢也可能在阻塞性睡眠呼吸暂停综合征和神经系统损伤之间的因果链中起着重要作用。 葡萄糖稳态因此，该提案的首要目标是描述脂肪畸变的特征 OSA的代谢。为了实现这一目标，我们将采用非常独特的 用于代谢表型分析和确定脂肪代谢、骨骼和脂肪 组织酶活性和Toll样受体（TLR）信号传导作为OSA中代谢功能障碍的介质。 此外，我们还将研究参与β-氧化的几种关键骨骼肌酶的活性， 如酰基辅酶A合酶（ACS）、肉毒碱棕榈酰转移酶-1（CPT-1）、β-羟酰基辅酶A 在OSA中，β-HAD和柠檬酸合酶（CS）被改变。最后，我们建议审查 OSA是否通过降低脂蛋白脂酶活性来干扰细胞外甘油三酯水解 (LPL)它调节各种组织中FFA的供应，用于储存或氧化。以下两个具体 提出了目标。目的1：评估OSA的严重程度是否与年龄、性别、种族和肥胖无关， 与以下改变相关：（1）全身脂解和游离脂肪酸（FFA）氧化;（2）皮下 脂肪组织脂解;（3）骨骼肌酶（ACS、CPT-1、HAD和CS）和TLR 2/TLR 4活性 （4）LPL在骨骼肌和脂肪组织中的活性。目的2：确定治疗是否 气道正压通气（PAP）治疗OSA的效果：（1）全身脂肪分解， FFA氧化;（2）皮下脂肪组织脂解;（3）骨骼肌酶（ACS，CPT-1， （4）骨骼肌和脂肪组织中的LPL活性。 这些目标的完成将增加对OSA如何改变葡萄糖和脂肪的迫切需要的机制的见解 代谢并帮助开辟新的治疗策略（即，脂肪分解的中断），这可能会减少 特别是在那些不能使用PAP治疗的患者中，OSA造成的代谢负担。

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.