PROTEOMIC STUDY OF HEPATIC METABOLISM REGULATED BY HYPOTHALAMIC PATHWAYS

Battelle Pacific Northwest Laboratories, Richland WA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The medio-basal hypothalamus (MBH) plays a pivotal role in the control of hepatic glucose homeostasis. The MBH senses circulating nutrients like glucose and fatty acids as well as hormones like leptin and insulin and thus assesses the energy state of the organism. When circulating levels of nutrients and insulin are rising during the postprandial state, pathways descending from the MBH are activated and hepatic glucose production (hGP) is suppressed. In the insulin resistant (IR) state insulin fails to suppress hepatic glucose production (hGP) which is partly explained by a loss of the MBH control of hGP. The molecular events that take place in peripheral tissues by the activation of these central pathways are poorly understood. The overall goal of this proposal is to utilize high sensitivity, high resolution LC-MS quantitative proteomics from the resource to identify differences in protein levels in total tissue as well as subcellular compartments (including cytosolic, mitochondria and membrane fractions) that are induced by the activation of the MBH. We aim to identify differences in protein abundances as well as serine/threonine phosphorylation differences in several subcellular extracts by applying the advanced proteomics technologies. Our goal is to identify key molecular pathways in liver tissue that exert control of lipid and glucose metabolism. These studies have the potential to facilitate the discovery of new therapeutic targets that decrease insulin resistance and avert or ameliorate type 2 diabetes. The proteomic data will serve the preliminary data for NIH R01 application as well as for future publications.