Energy Expenditure in HIV Lipodystrophy

描述（由申请人提供）：HIV脂肪营养不良（LD）是HIV感染及其治疗的常见并发症。其特征在于广泛的皮下脂肪损失，并与胰岛素抵抗、糖尿病和高脂血症有关。我们发现HIV LD也与休息（REE）和每日总能量消耗增加有关。在先天性LD中也发现了EE的这种增加，但发病机制尚不清楚。然而，我们最近发现，HIV LD受试者对短期喂养不足和过度喂养的反应是独特的，REE分别显著减少和增加。艾滋病毒LD和它的反应性的变化，在热量摄入的REE升高可能代表适应性产热在这一重要组成部分的每日总能量消耗的真实形式。这种适应性产热可能是对不能以正常方式储存甘油三酯燃料的反应，继发于皮下脂肪组织的广泛损失/功能障碍。深入了解这种适应的机制将与体重调节以及超重和肥胖的流行状况有很大的相关性。在本申请中，我们将确定与HIV感染者和健康对照组相比，交感神经系统是否对HIV LD和高代谢受试者的REE支持更有贡献。我们还将确定病例与对照组骨骼肌中线粒体解偶联是否增加。增加线粒体解偶联消耗热量作为热量，并导致增加REE。因此，这可能是HIV LD高代谢背后的潜在机制。除了这些机制研究，我们还将测试高脂肪和高碳水化合物过量喂养期间HIV LD患者的能量反应和底物氧化模式。我们推测，过量摄入这两种大量营养素将与LD患者的REE和TEE显著增加相关，但在对照组中则不然。我们还预计，高脂肪的过度喂养将导致显着增加脂肪氧化在LD主题，但不是在控制。最后，我们将确定HIV LD是否与氧化应激增加有关。HIV LD是一种高代谢状态，由于活性氧是氧消耗的正常副产品，因此这种综合征可能与氧化应激增加有关。这在糖尿病和动脉粥样硬化血管疾病风险增加的人群中尤其相关，因为氧化应激可能在这些疾病过程中发挥作用。公共卫生相关性：HIV脂肪营养不良患者的皮下脂肪组织数量异常低且功能障碍。他们也有一个高于正常的代谢率。这种增加的代谢率可能是一种“适应性产热”的形式。换句话说，这些患者可能会将卡路里转化为热量，而不是储存它们，因为他们的皮下脂肪组织不能将卡路里储存为脂肪。如果能更好地理解这一点，我们的发现将与肥胖领域有广泛的相关性，并可能为这一常见问题开辟新的治疗途径。

DESCRIPTION (provided by applicant): HIV lipodystrophy (LD) is a common complication of HIV infection and its therapy. It is characterized by extensive subcutaneous fat loss and is associated with insulin resistance, diabetes and hypertriglyceridemia. We have found that HIV LD is also associated with increased resting (REE) and total daily energy expenditure. Such increases in EE have also been found in congenital forms of LD but the pathogenesis is unknown. However, we have recently shown that subjects with HIV LD uniquely respond to short-term under- and overfeeding with significant decreases and increases in REE, respectively. The elevated REE of HIV LD and its responsiveness to changes in caloric intake may represent true forms of adaptive thermogenesis in this important component of total daily energy expenditure. This adaptive thermogenesis may be a response to an inability to store triglyceride fuel in a normal manner secondary to extensive loss/dysfunction of subcutaneous adipose tissue. Insights into the mechanism(s) underlying this adaptation would have great relevance to weight regulation in general and to the epidemic conditions of overweight and obesity. In this application, we will determine if the sympathetic nervous system contributes more to the support of REE in subjects with HIV LD and hypermetabolism compared to HIV-infected and healthy controls. We will also determine if there is increased mitochondrial uncoupling in the skeletal muscle of cases vs controls. Increased mitochondrial uncoupling dissipates calories as heat and leads to increased REE. Therefore, this could a potential mechanism behind the hypermetabolism of HIV LD. In addition to these mechanistic studies, we will also test the energetic response to and substrate oxidation pattern during both high-fat and high-carbohydrate overfeeding in patients with HIV LD. We hypothesize that overfeeding of both macronutrients will be associated with significant increases in REE and TEE in those with LD but not in controls. We also anticipate that high-fat overfeeding will lead to significant increases in fat oxidation in LD subjects but not in controls. Finally, we will determine if HIV LD is associated with increased oxidative stress. HIV LD is a hypermetabolic state, and since reactive oxygen species are a normal byproduct of oxygen consumption, it is plausible that this syndrome will be associated with increased oxidative stress. This is especially relevant in this population already at increased risk of diabetes and atherosclerotic vascular disease as oxidative stress may play a role in these disease processes. PUBLIC HEALTH RELEVANCE: Patients with HIV lipodystrophy have both abnormally low amounts and dysfunction of their subcutaneous adipose tissue. They also have a higher then normal metabolic rate. This increased metabolic rate may be a form of "adaptive thermogenesis". In other words, these patients may convert calories to heat instead of storing them because their subcutaneous adipose tissue cannot store the calories as fat. If this could be better understood, our findings would have broad relevance to the field of obesity in general and could open up new avenues of treatment for this common problem.