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

肌肉减少症是一种与衰老有关的肌肉质量和力量的逐渐丧失， 个体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。他们的组合被称为肌肉减少性肥胖，并与最高的 残疾、死亡和医疗费用增加的风险。尽管它的相关性，治疗 肌肉减少性肥胖症是不可用的，导致这种情况的分子机制 并不完全理解。Ghrelin是GHSR-1a受体的内源性配体， 调节肌肉和脂肪质量的食欲激素。我们最近发现，生长激素释放肽缺失是 足以防止老年小鼠的肌肉减少性肥胖。它减弱pAMPK的降低， 增加IIa型（氧化）肌肉纤维的数量，同时也预防肥胖。此外，我们最近 显示生长激素释放肽在肌肉和脂肪组织中发挥其作用，至少部分地，独立于 GHSR-1a。然而，介导这些影响的机制还不完全清楚。 本提案的总体目标是描述胃饥饿素介导作用的机制 及其受体（GHSR-1a）在肌肉减少性肥胖中的作用，并评估GHSR-1a 在这种情况下，拮抗作用作为一种治疗方法。我们假设在啮齿动物模型中- 相关的肌肉减少性肥胖：1）Ghrelin通过以下方式诱导骨骼肌功能障碍：a）引起线粒体 功能障碍和纤维类型分布变化，和B）调节脂肪酸代谢和异位脂质 2）Ghrelin通过调节食物摄入、产热和脂肪酸来诱导脂肪积累 GHSR-1a拮抗/缺失将部分预防肌肉减少性肥胖 通过上调AMPK依赖的途径，调节肌肉和线粒体中的纤维类型分布， 骨骼肌和脂肪组织的功能和脂质代谢。具体目标是： 1)表征肌萎缩症中肌中ghrelin的调节作用的机制 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 将评估身体组成、食物摄入、运动活动和肌肉性能。肌肉质量， 纤维类型和AMPK活化、线粒体功能、脂肪酸代谢和脂质储存的标志物 将在肌肉中进行评估。还将测试长期胃饥饿素施用和配对喂养的效果。 2)Ghrelin对肥胖和脂肪细胞影响的机制研究 在肌肉减少性肥胖中的作用将评价年轻、中年和老年成年ghrelin WT和KO小鼠 能量消耗、身体组成、食物摄入和运动活动。分子介质 产热、线粒体功能、AMPK激活和脂质代谢将以白色和 棕色脂肪垫还将测试长期胃饥饿素施用和配对喂养的效果。 3)确定GHSR-1a介导ghrelin作用的程度。青年、中年和老年 评价成年GHSR-1a WT和KO小鼠的身体组成、食物摄入、运动活动 肌肉性能和能量消耗。肌肉和脂肪中的纤维分型和分子标记将是 如上文目标1和2所述进行研究。在GHSR-1a WT和GHSR-1a WT中长期给予生长素释放肽的作用 KO和Ghrelin WT和KO中GHSR-1a的药理学抑制（使用GHSR-1a拮抗剂HM 04） 也将受到考验。为了确定AMPK在这种情况下的作用，还将在WT中测试HM 04的作用。 和在骨骼肌中表达失活形式AMPKα的AMPKα 2 i转基因小鼠。 表征介导ghrelin和GHSR-1a作用的机制是新颖的和相关的，因为 生长素释放肽、GHSR-1a激动剂和拮抗剂处于临床开发中。更好地了解他们 作用机制将使我们能够开发新的治疗肌肉减少性肥胖症的方法。

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.