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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059767-02
Application #
6382023
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2000-09-15
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$258,581
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Rahman, Shaikh M; Baquero, Karalee C; Choudhury, Mahua et al. (2016) C/EBP? in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis. Atherosclerosis 250:172-9
Martin-Murphy, Brittany V; You, Qiang; Wang, Hong et al. (2014) Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS One 9:e80949
Rahman, Shaikh M; Choudhury, Mahua; Janssen, Rachel C et al. (2013) CCAAT/enhancer binding protein ? deletion increases mitochondrial function and protects mice from LXR-induced hepatic steatosis. Biochem Biophys Res Commun 430:336-9
Choudhury, Mahua; Friedman, Jacob E (2012) Epigenetics and microRNAs in preeclampsia. Clin Exp Hypertens 34:334-41
Qadri, Ishtiaq; Choudhury, Mahua; Rahman, Shaikh Mizanoor et al. (2012) Increased phosphoenolpyruvate carboxykinase gene expression and steatosis during hepatitis C virus subgenome replication: role of nonstructural component 5A and CCAAT/enhancer-binding protein ?. J Biol Chem 287:37340-51
Rahman, Shaikh M; Janssen, Rachel C; Choudhury, Mahua et al. (2012) CCAAT/enhancer-binding protein ? (C/EBP?) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice. J Biol Chem 287:34349-60
McCurdy, Carrie E; Schenk, Simon; Holliday, Michael J et al. (2012) Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice. Diabetes 61:2495-505
Kendrick, Agnieszka A; Choudhury, Mahua; Rahman, Shaikh M et al. (2011) Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J 433:505-14
Attia, Ramy R; Sharma, Pragya; Janssen, Rachel C et al. (2011) Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by CCAAT/enhancer-binding protein beta (C/EBPbeta). J Biol Chem 286:23799-807
Choudhury, Mahua; Qadri, Ishtiaq; Rahman, Shaikh Mizanoor et al. (2011) C/EBP? is AMP kinase sensitive and up-regulates PEPCK in response to ER stress in hepatoma cells. Mol Cell Endocrinol 331:102-8

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