Resolving the growth-promoting and lipid catabolic actions of growth hormone

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The means by which hormones elicit multiple effects in animals remains a central question in the field of chemical signalling. For example, growth hormone (GH) is known to regulate several processes, including aspects of growth, metabolism, reproduction, osmoregulation, immune function, and behaviour, yet the mechanisms that underlie these diverse processes are not fully understood. In this project, rainbow trout will be used as a model organism to evaluate two disparate actions of GH: 1) growth promotion, an anabolic process, and 2) breakdown and mobilization of stored lipid reserves (lipolysis), a catabolic process. Fish such as trout provide an opportune system in which to examine this problem because they grow throughout their life (indeterminate growth) and display a diverse lipid storage strategy that results in the colocalization of important growth-promoting [i.e., insulin-like growth factor-1 (IGF-1) synthesis and secretion] and lipid storage/lipolysis processes within the same cell types (e.g., liver cells, a main lipid store as well as the principal site of IGF-1 synthesis). The 4-year plan of work will integrate several approaches (e.g., physiological, cellular, biochemical/molecular/ genomic) and address the problem in three phases. In the first phase, we will characterize GH receptor (GHR) binding properties and assess its selectivity for different hormones that are structurally similar to GH (e.g., prolactin). In phase 2, we will identify the cell signal pathways activated by GH and how these pathways are reprogrammed by an anabolic to catabolic shift. This will establish GHR-effector pathway linkages. In phase 3, we will elucidate linkages between signal pathways and specific biological responses, and specifically evaluate differential activation of growth-promotion (e.g., IGF-1 production) and lipolysis. This project will fundamentally advance our understanding of the coordination of growth and metabolism by elucidating for the first time the means by which cells get reprogrammed to repress the growth-promoting actions of GH to enable its lipolytic actions. In addition, this project will provide novel information about the mechanisms by which GH stimulates lipolysis (via hormone-sensitive lipase activation and/or synthesis) and about the regulation of GHRs and GHR-effector system linkages. While this work pertains specifically to fish, it will have broad relevance to understanding the nature and evolution of growth-metabolism interactions in vertebrates generally. This project will have numerous other broad impacts. It will expand critical research infrastructure in North Dakota, which serves to diversify the nation's scientific enterprise. It also will afford research education and training opportunities to graduate and undergraduate students, including members of underrepresented groups. The project will specifically engage faculty and students of the state's tribal colleges through curriculum development, workshops, and summer camps. These activities that will lead to a collaborative student-centered research project at a tribal college. The findings also will have application to enhancing agricultural production of fish, poultry, and domestic livestock, as well as to the detection and treatment of various growth/metabolic disorders in animals and humans.