Regulation of peripheral metabolism by ghrelin.

胃饥饿素是一种刺激食欲的激素，由胃产生，在正常进餐前释放。生长素还能有效刺激生长激素（GH）的释放。这混淆了ghrelin在体内的直接代谢作用的解释，因为生长激素本身有许多代谢结果。我们认为胃饥饿素可以作为一种信号，为骨骼肌和脂肪（脂肪）储存等组织准备摄取和代谢将被摄入的营养物质（葡萄糖和脂肪酸）。关于胃饥饿素对骨骼肌和脂肪组织的直接代谢作用知之甚少。我们的实验室使用大鼠分离的骨骼肌和脂肪组织来研究激素对这些组织代谢过程的直接影响。我们的实验室是第一个证明胃饥饿素可以直接刺激脂肪酸代谢，为肌肉提供能量的实验室。重要的是，在血液中饱和脂肪酸增加的时期，这种脂肪代谢的刺激可能保护胰岛素信号通路的功能。众所周知，饱和脂肪会损害胰岛素促进葡萄糖摄取和利用的能力。有趣的是，饥饿素的这种保护作用在长期高脂肪饮食的啮齿动物中消失了。这意味着饥饿素耐药性的发展，是一个新的发现。虽然高脂肪饮食的消耗似乎是一个促成因素，但我们认为，被关在笼子里的动物的极端久坐行为更为重要，因为包括运动训练可以防止胃饥饿素耐药性的发展。最后，我们的实验室已经证明，胃饥饿素可以减缓通常由肾上腺素激活的脂肪组织中脂肪分解的速度。其生理意义尚不清楚，但可能是1)起到“刹车”的作用，防止过高的脂肪分解率，或2)为饭后的脂肪储存准备脂肪组织。目前的建议将促进我们对胃饥饿素在离体大鼠肌肉和脂肪组织中的直接代谢作用的理解。具体目标将是研究i) ghrelin作用的信号机制（受体，蛋白质）；Ii)胃饥饿素刺激肌肉利用脂肪能力的细胞过程；Iii)肌肉中胃饥饿素耐药性的发展及其意义；iv)脂肪组织中胃饥饿素对脂肪分解和再合成的调控。这些研究将促进我们对胃饥饿素的理解，并探索其作为代谢调节剂的新作用，而不仅仅是一种“饥饿激素”。我们建议使用雄性和雌性大鼠的组织进行实验，因为葡萄糖和脂肪代谢的性别差异是众所周知的。提出的实验工作具有原创性和新颖性，将为HQP提供良好的培训环境，并巩固我的实验室作为少数几个推进胃饥饿素研究领域的实验室之一的地位。

Ghrelin is an appetite-stimulating hormone that is produced by the stomach and released prior to regular mealtimes. Ghrelin also potently stimulates growth hormone (GH) release. This confounds the interpretation of ghrelin's direct metabolic effects in vivo as GH itself has numerous metabolic outcomes. We believe that ghrelin may act as a signal to prepare tissues such as skeletal muscle and adipose (fat) stores for the uptake and metabolism of nutrients (glucose and fatty acids) which will be ingested. Very little is known about the direct metabolic effects of ghrelin on skeletal muscle and adipose tissue. Isolated skeletal muscle and adipose tissue from rats are used in our lab to study the direct effects of hormones on metabolic processes in these tissues. Our lab was the first to demonstrate that ghrelin can directly stimulate the metabolism of fatty acids to provide energy in muscle. Importantly, this stimulation of fat metabolism may protect the functioning of the insulin signalling pathway during periods where saturated fatty acids in the blood are increased. Saturated fats are known to impair the ability of insulin to promote the uptake and use of glucose. Interestingly, this protective effect of ghrelin is lost in rodents consuming a prolonged high-fat diet. This implies the development of ghrelin resistance and is a novel discovery. Although the consumption of a high-fat diet appears to be a contributing factor, we believe that the extreme sedentary behaviour of the animals which are housed in cages is more important, as the inclusion of exercise training prevents the development of ghrelin resistance. Finally, our lab has shown that ghrelin can slow the rate of fat breakdown in adipose tissue normally activated by adrenaline. The physiological significance is unclear but may be i) to act as a "brake" preventing excessively high rates of fat breakdown, or ii) to prepare adipose tissue for the storage of fat following a meal. The current proposal will advance our understanding of ghrelin's direct metabolic effects in isolated rat muscle and adipose tissue. The specific aims will be to study i) the signalling mechanisms (receptors, proteins) underlying ghrelin's effects; ii) the cellular processes underlying ghrelin's ability to stimulate fat utilization by muscle; iii) the development of ghrelin resistance in muscle and its' significance; and iv) the regulation of fat breakdown and resynthesis by ghrelin in adipose tissue. These studies will advance our understanding and examine new roles of ghrelin as a regulator of metabolism beyond its identification as a "hunger hormone". We propose to conduct experiments using tissue from both male and female rats, as sex differences in the metabolism of glucose and fat are well known. The proposed experimental work is original and novel and will provide an excellent training environment for HQP, as well as solidify my lab's position as one of the few to advance this area of ghrelin research.