| A worldwide obesity epidemic has ignited much interest in the metabolism field as novel therapeutics for maintaining euglycemia are required to combat a growing unmet need. Uncontrolled hepatic glucose production, insulin resistance, and hepatic steatosis are among the major complications associated with obesity. Intracellular Ca2+ signals have well-established importance in the cascade of events linking hormonal signaling to certain metabolic processes. This thesis was undertaken to understand the functional involvement of the intracellular Ca2+ release channel, the inositol 1,4,5 trisphosphate receptor (InsP3R), in hepatic metabolic pathways.;There are three known isoforms of the InsP3R, with varying tissue and subcellular expression patterns. In the liver, the predominant isoforms are InsP3R-I and ---II with the latter residing in a highly concentrated cluster on the endoplasmic reticuIum under the canalicular membrane. Conversely, InsP3R-I is diffusely found throughout the cytoplasm and in the perinuclear space. Recently, InsP3Rs have emerged as a protein of interest in metabolic pathways, however isoform-specific effects are not well characterized.;Here, I find that expression and function of the InsP3Rs are altered in obese mice. I report that mice lacking InsP3R-II have normal rates of hepatic glucose production. Likewise, InsP3R-II deletion does not affect insulin sensitivity or hepatic steatosis. These results suggest that InsP3R-II's responsibility in the liver is to regulate bile secretion and the particular InsP3R isoform does not have a critical contribution to metabolic processes.;I also found that liver-specific deletion of InsP3R-I did not alter rates of hepatic glucose production. However, loss of hepatic InsP 3R-I did confer insulin sensitivity and protection from hepatic steatosis. These are novel findings which imply that InsP3R-I's subcellular localization positions the channel on the ER membrane in cellular compartments where relevant metabolic processes take place. By utilizing genetic mouse models and reliable experimental techniques, our findings clarify inconsistencies in the literature regarding the role of InsP3Rs in metabolism.;Collectively, these results provide new evidence for isoform specificity and subcellular specificity in hepatic InsP3R-mediated Ca 2+ signaling. Through this work, I provide a fuller understanding of both physiological and pathophysiological Ca2+-sensitive metabolic processes. Given the recent interest in targeting the InsP 3R and its downstream pathways for the treatment of metabolic disease, the results presented here have important implications for the development of novel therapeutics. |
