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The Role of the CRTC Family of CREB Coactivators in Glucose Homeostasis /

  • Author(s): Hogan, Meghan Fennell
  • et al.
Abstract

Obesity and its associated health issues are reaching epidemic levels worldwide. There are many reasons for this increase in metabolic diseases including environmental and lifestyle changes. However, there are also many biological mechanisms that shift the energy homeostasis of a system to a dysregulated state, often resulting in obesity or diabetes. One of these mechanisms that contribute to the rise of blood glucose levels and eventual failing of insulin producing beta-cells in the pancreas is hepatic gluconeogenesis. The hormones that regulate this process include insulin and glucagon. Glucagon acts through the secondary messenger cAMP, stimulating the cAMP Response Element Binding Protein (CREB) and its associated co- activators, the CRTCs to enhance gluconeogenic enzyme transcription. It has been clear that CRTC2 plays a role in this process, but this dissertation provides evidence for overlapping roles of CRTC2 and CRTC3, explaining past observations regarding modest phenotypes of CRTC2 null mice. Additionally, we show here that chronic expression of a liver expressed, constitutively active CRTC2 through an adeno-associated virus that upregulated hepatic gluconeogenesis is able to lead to an insulin resistant phenotype that is eventually compensated for by the upregulation of IRS2, a CREB target gene

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