The long-term goal of this research is to investigate a molecular target that regulates gluconeogenesis and improves glucose control during diabetes. The hyperglycemia of diabetes is linked to increased gluconeogenesis and impaired glucose uptake in peripheral tissues, however the molecular signals responsible for integrating these pathways are unclear. We hypothesize that the transcription factor C/EBPbeta can control gluconeogenesis and insulin sensitivity by integrating the hormonal response to glucagon and glucocorticoids at the level of gene transcription. Evidence resented that lack of C/EBPbeta affects critical metabolic processes that regulate liver gluconeogenesis and lipolysis, resulting in hypoglycemia and decreased fatty acid mobilization. The absence of C/EBPbeta enhances whole-body insulin sensitivity, and decreases gluconeogenesis and PEPCK gene transcription during streptozotocin diabetes, indicating that deleting C/EBPbeta may have anti-diabetic effects. The objective of this research is to exploit the C/EBPbeta knockout mice as a tool to understand the molecular mechanisms that regulate glucose homeostasis during diabetes, with a long term-term goal of developing novel strategies to reduce hyperglycemia.
In Specific Aim 1 we will determine the role of adipose tissue C/EBPbeta on gluconeogenesis and peripheral insulin sensitivity by creating transgenic AP2-C/EBPbeta mice expressing C/EBPbeta selectively in adipocytes.
In Specific Aim 2 we will define the liver-specific role of C/EBPbeta on gluconeogenesis, insulin sensitivity, and gene expression by selectively replacing liver C/EBPbeta using adenovirus-mediated gene delivery in C/EBPbeta -/- mice.
In Specific Aim 3, we will determine the effect of C/EBPbeta knockout on resistanCe to extreme obesity and diabetes by breeding C/EBPbeta -/- mice together with genetically obese-diabetic db/db mice. The double homozygous mice will be characterized for changes in gluconeogenesis, obesity, and insulin sensitivity by tracer infusion. Lastly, we will use primary hepatocytes from wild type and C/EBP beta-/- mice to develop a detailed profile of cAMP during a time course of administration glucagon, forskolin, and phosphodiesterase inhibitors. We will correlate the changes in cAMP with gene transcription, glycogen breakdown, and gluconeogenesis.
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