Novel Role of ??-Adrenergic Receptors to Activate the mTOR-S6K1 Signaling Pathway

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DESCRIPTION (provided by applicant): Activation of ¿-adrenergic receptors (¿ARs) in adipocytes by E/NE increases cAMP levels and cAMP- dependent protein kinase (PKA) activity. PKA phosphorylates several key targets that promote lipolysis to release free fatty acids and glycerol. Opposing this catabolic response is insulin, which stimulates lipogenesis and fuel conservation in adipocytes. Insulin is also an important growth promoter though its ability to activate the mTOR-S6K1 pathway. mTOR is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues such as growth factors, and nutrients such as glucose and amino acids. Consistent with their opposing functions in fat, the insulin and catecholamine systems also antagonize eachother's signaling pathways at several levels, thus providing dynamic and sensitive control of energy needs. In addition to the traditional role of ¿ARs in the stimulation of lipolysis and suppression of insulin- action, our new studies unexpectedly show that ¿ARs activate the mTOR-S6K1 pathway in a cAMP and PKA dependent manner. This activity can be observed in human and rodent fat cells, white and brown adipocytes. This pathway is principally involved in the regulated translation of specific sets of mRNAs. The fat cell is increasingly recognized as an important source of peptide adipokines, angiogenic factors, and perhaps even other peptide neurotransmitters, but there is limited understanding of how these factors are synthesized, regulated or secreted. The studies proposed here in this R21 Pilot and Feasiblility project will test the following two specific hypotheses: (1) The role of ¿AR and cAMP-stimulated S6K1 activity in adipocytes is to selectively stimulate the translation of a set of mRNAs that are distinct from those regulated by insulin, and we propose to identify these transcripts. The approach taken involves polysome fractionation followed by microarray profiling of differentially redistributed transcripts. (2) The role of ¿AR and cAMP-stimulated S6K1 activity in adipocytes is to desensitize the insulin-signaling pathway, and this is achieved through Ser phosphorylation of IRS-1 by S6K1. Given the integrative role of adipose tissue in the etiology of metabolic syndrome, this exploratory research project provides both an opportunity to expand the terrain from which new targets for intervention in metabolic disease might be identified, as well as promote our basic understanding of the cell biology of the adipocyte. PUBLIC HEALTH RELEVANCE: The continuing escalation in the incidence of Type II diabetes in the US (and around the world) is placing an enormous burden on the health care system, on worker productivity and on quality of life for those afflicted. We know a great deal of information about the steps in the cascade of intracellular actions of insulin and how they tend to be perturbed in the early phases of the development of Type II diabetes. We know that the ability of fat cells to store energy and to regulate its release is an important component of proper nutrient partitioning in the body. However the fat cell is not only a bank in which excess metabolic energy is stored as currency for use during times of caloric deficit, but it is also an important source of protein hormones. These include hormones to control appetite, proper insulin action in other tissue such as muscle, and fat is even a source of factors to regulate blood vessel growth and immune responses. There is also increasing appreciation that fat cells can also be net consumers of energy and thus have the potential to even fight obesity. However, compared to what we know about fat storage and release, we know comparatively very little about the control of fat cell-derived hormones and signaling molecules, which are themselves controlled by circulating hormones such as insulin and adrenaline. The purpose of this proposal is to test new ideas that developed from unexpected new findings in our laboratory, in which we propose to demonstrate that there are unique processes in fat cells that control non-overlapping sets of protein production, and we postulate that some of these differentially regulated proteins will code for these fat cell-derived hormones.