Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Klaus H. Kaestner

Second Advisor

Mitchell A. Lazar

Abstract

Excessive hepatic glucose production is a hallmark of insulin resistance in type 2 diabetes. The cAMP-responsive transcription factor cAMP-responsive element binding protein (CREB), thought to be a key activator of the hepatic gluconeogenic gene regulation program, has been suggested as therapeutic target to reduce glucose output by the liver. Here, I test directly the requirement for hepatocytic CREB for the maintenance of glucose homeostasis utilizing Cre-loxP for conditional, cell-type specific gene ablation. Strikingly, I find no difference in fed and fasted glucose levels, or glucose, insulin, and glucagon tolerance in mice fed normal chow or a high-fat diet in hepatocyte Creb-null mice compared to controls. In addition, mRNA levels of liver specific genes, including several CREB target genes involved in gluconeogenesis, were not affected by CREB deficiency in the liver. In conclusion, my data indicate that CREB has no non-redundant functions in hepatic glucose metabolism, and is therefore not likely to be a useful target for the development of anti-diabetic drugs.

Furthermore, lipolysis and thermogenesis are regulated by catecholamines signaling via β-adrenergic receptors in adipose tissue and a role for the CREB in adipocyte function had been suggest by previous studies. However the role of CREB in adipose tissue had never been evaluated in vivo. Here, I test directly the requirement for adipocyte CREB for lipolysis and thermogenesis using the Cre-loxP system for adipocyte-specific ablation of Creb in mice. Loss of adipocytic Creb lead to a moderate decrease in fasting-induced lipolysis in adipose tissue. Strikingly, the adipocytic transcriptome was not globally affected by ablation of Creb. In addition, cold temperature and cAMP signaling-induced thermogenesis and white-to-beige adipocyte conversion were not changed in adipocyte specific Creb-null mice compared to controls. In conclusion, my data indicate that CREB has no non-redundant functions in thermogenesis, but contributes to the regulation of fasting-induced lipolysis. The underlying mechanism of reduced fasting-induced lipolysis in adipocytic CREB-deficient mice will need to be explored further.

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