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. ? ? ?
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