The Role of Ghrelin and the GHSR-1a receptor in Sarcopenic Obesity

骨质疏松症是一种与衰老相关的肌肉质量和力量的进行性丧失，在25%的老年人中存在 个人。肥胖在这个年龄段也很常见，这两种情况都会导致残疾增加， 发病率和死亡率。他们的组合被称为骨质疏松性肥胖，并与最高 残疾、死亡和医疗费用增加的风险。尽管它具有相关性，但治疗 骨质型肥胖是不可用的，导致这种情况的分子机制 是不完全理解的。Ghrelin是GHSR-1a受体的内源性配体，是一种 调节肌肉和脂肪质量的促食欲激素。我们最近发现Ghrelin缺失是 足以防止老年小鼠出现骨质疏松性肥胖。它能减弱pAMPK的下降，并 增加IIa(氧化)型肌肉纤维的数量，同时也防止肥胖。另外，我们最近 表明Ghrelin在肌肉和脂肪组织中发挥作用，至少部分地不依赖于 GHSR-1a。然而，调节这些效应的机制还不完全清楚。 本提案的总体目标是描述调节Ghrelin作用的机制 及其受体(GHSR-1a)在肌肉源性肥胖中的作用，并评估其潜在的作用 在这种情况下，对抗是一种治疗方法。我们假设在啮齿动物的年龄模型中- 相关的骨质源性肥胖：1)生长激素通过以下方式导致骨骼肌功能障碍：a)引起线粒体 功能障碍和纤维类型分布变化，以及b)调节脂肪酸代谢和异位脂质 沉积；2)Ghrelin通过调节食物摄入量、产热作用和脂肪酸诱导脂肪堆积 脂肪组织中的代谢，以及3)GHSR-1a拮抗/缺失将部分防止肌源性肥胖 通过上调调节肌肉和线粒体中纤维类型分布的AMPK依赖的通路 骨骼肌和脂肪组织的功能和脂肪代谢。具体目标是： 1)研究Ghrelin在骨骼肌抑制中的作用机制 肥胖。年轻(8月龄)、中年(18月龄)和老年(28月龄)成年Ghrelin WT&KO小鼠 将根据身体成分、食物摄入量、运动能力和肌肉表现进行评估。肌肉质量， AMPK激活、线粒体功能、脂肪酸代谢和脂肪储存的纤维类型和标志物 将在肌肉中进行评估。长期服用Ghrelin和配对喂养的效果也将得到测试。 2)确定Ghrelin对肥胖和脂肪细胞影响的机制 在骨肉源性肥胖中的作用。年轻、中年和老年Ghrelin WT和KO小鼠将被评估 能量消耗、身体成分、食物摄入量和运动活动。血管紧张素转换酶分子介体 发热、线粒体功能、AMPK激活和脂质代谢将在白色和 棕色肥大的护垫。长期服用Ghrelin和配对喂养的效果也将得到测试。 3)确定GHSR-1a在多大程度上调节Ghrelin的作用。青年、中年和老年 成年GHSR-1a WT和KO小鼠将被评估身体成分，食物摄入量，运动活动， 肌肉表现和能量消耗。肌肉和脂肪的纤维分型和分子标记将是 如上文目标1和2所示进行了研究。长期应用Ghrelin对GHSR-1a西药和西药的影响 KO，以及GHSR-1a(使用GHSR-1a拮抗剂HM04)对Ghrelin WT和KO的药理抑制作用 也将接受测试。为了确定AMPK在此设置中的作用，还将在WT中测试HM04的效果 以及在骨骼肌中表达失活形式的AMPKα2I转基因小鼠。 表征介导Ghrelin和GHSR-1a作用的机制是新的和相关的，因为 Ghrelin、GHSR-1a激动剂和拮抗剂正在临床开发中。更好地了解他们的 作用机制将使我们能够开发治疗骨肉源性肥胖的新疗法。

Sarcopenia, a progressive loss of muscle mass and strength associated with aging, is present in 25% of older individuals. Obesity is also very common in this age group and both conditions lead to increased disability, morbidity and mortality. Their combination is termed sarcopenic obesity and is associated with the highest risks of disability, mortality and increased healthcare costs. Despite its relevance, treatments for sarcopenic obesity are not available and the molecular mechanisms leading to this condition are incompletely understood. Ghrelin, the endogenous ligand for the GHSR-1a receptor, is an orexigenic hormone that regulates muscle and fat mass. We recently showed that ghrelin deletion is sufficient to prevent sarcopenic obesity in older mice. It attenuates the decrease in pAMPK and increases the number of type IIa (oxidative) muscle fibers, while also preventing obesity. Also, we have recently shown that ghrelin exerts its effects in muscle and in adipose tissue, at least in part, independently of the GHSR-1a. However, the mechanisms mediating these effects are incompletely understood. The overall goals of this proposal are to characterize the mechanisms mediating the role of ghrelin and its receptor (GHSR-1a) in sarcopenic obesity, and to evaluate the potential for GHSR-1a antagonism as a therapeutic approach in this setting. We hypothesize that in a rodent model of age- related sarcopenic obesity: 1) Ghrelin induces skeletal muscle dysfunction by: a) Causing mitochondrial dysfunction and fiber type distribution changes, and b) Modulating fatty acid metabolism and ectopic lipid deposition; 2) Ghrelin induces fat accumulation by modulating food intake, thermogenesis, and fatty acid metabolism in adipose tissue, and 3) GHSR-1a antagonism/deletion will partially prevent sarcopenic obesity by upregulating AMPK-dependent pathways that regulate fiber type distribution in muscle and mitochondrial function and lipid metabolism in skeletal muscle and adipose tissue. The specific aims are: 1) Characterize the mechanisms mediating the effects of ghrelin in muscle in sarcopenic obesity. Young (8-month old), middle age (18-month old) and old (28-month old) adult ghrelin WT&KO mice will be evaluated for body composition, food intake, locomotor activity and muscle performance. Muscle mass, fiber type and markers of AMPK activation, mitochondrial function, fatty acid metabolism, and lipid storage will be evaluated in muscles. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 2) Determine the mechanisms mediating the effects of ghrelin on adiposity and adipocyte function in sarcopenic obesity. Young, middle age and old adult ghrelin WT and KO mice will be evaluated for energy expenditure, body composition, food intake and locomotor activity. Molecular mediators of thermogenesis, mitochondrial function, AMPK activation and lipid metabolism will be probed in white and brown fat pads. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 3) Establish the extent to which GHSR-1a mediate the effects of ghrelin. Young, middle age and old adult GHSR-1a WT and KO mice will be evaluated for body composition, food intake, locomotor activity, muscle performance and energy expenditure. Fiber typing and molecular markers in muscle and fat will be studied as indicated in aims 1 and 2 above. The effect of chronic ghrelin administration in GHSR-1a WT and KO, and pharmacological inhibition of GHSR-1a (using the GHSR-1a antagonist HM04) in ghrelin WT and KO also will be tested. To determine the role of AMPK in this setting, the effects of HM04 will also be tested in WT and AMPKα2i transgenic mice that express the inactive form AMPKα in skeletal muscle. Characterizing the mechanisms mediating the effects of ghrelin and GHSR-1a is novel and relevant because ghrelin, GHSR-1a agonists and antagonists are in clinical development. A better understanding of their mechanisms of action will allow us to develop novel therapies for sarcopenic obesity.