Regulation of peripheral metabolism by ghrelin.

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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.