The United States is experiencing an epidemic of obesity-driven metabolic disorders which is even greater in juvenile populations. The metabolic abnormalities accompanying obesity frequently involve inflammation, hyperlipidemia, and hyperglycemia, however the transcriptional mechanisms underlying these abnormalities remain poorly understood. Recent results from this laboratory in mice lacking CCAAT/Enhancer Binding Protein b have revealed a remarkable array of metabolic regulatory functions for C/EBPb, including significant effects on energy intake, gluconeogenesis, and triglyceride metabolism. The proposed research is based on the hypothesis that C/EBPb is required for regulating gluconeogenic and lipogenic responses in the liver and mediating aspects of leptin-mediated gene transcription yet to be described. The long-term goals of this proposal are to further characterize the metabolic effects of C/EBPb in liver and brain, to identify target genes and the regulatory mechanisms involved, and to understand the potential role of C/EBPb in development of fatty liver.
In Specific aim 1 we will generate tissue-specific knockout mice to determine the role of C/EBPb in liver and brain on resistance to obesity.
In Specific Aim 2, the biological consequences of the truncated isoforms of C/EBPb on triglyceride synthesis and metabolism will be examined in livers from transgenic and cell culture models. We will also examine whether PPARa is required for C/EBPb knockdown to inhibit hepatic lipogenesis using substrate metabolism, gene array, and PPAR knockout cell lines.
In Specific Aim 3 we will determine the metabolic consequences of over-expressing the activating (LAP) and liver inhibiting (LIP) form of C/EBPb on lipogenesis and gluconeogenesis in-vivo. Lastly, in Specific Aim 4 we will determine whether C/EBPb plays a role in the liver of obese children with fatty liver disease. Our studies will quantify lipid staining and address whether C/EBPb and other transcription factors involved in lipogenesis are over-expressed in the liver from obese subjects with NAFLD and NASH and their relationship to the lipid positive cells. The studies described in this proposal will have important clinical implications for understanding the pathways that control liver gluconeogenesis and lipogenesis and could open up new avenues for understanding mechanisms contributing to obesity, diabetes, and fatty liver disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059767-06
Application #
7271120
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2000-09-15
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$299,700
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
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
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
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

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