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Foxa2, metabolic function, insulin signaling, hypothalamus


The Forkhead box A2 transcription factor (Foxa2/HNF-3β) has been shown to be a key regulator of genes involved in the maintenance of glucose and lipid homeostasis in the liver, and is constitutively inactivated in several hyperinsulinemic/obese mouse models, thereby enhancing their metabolic phenotypes. Foxa2 is activated under fasting conditions, but is inhibited by insulin signaling via PI3K/Akt in a phosphorylation-dependent manner, which results in its nuclear exclusion. However, the mechanism and relative importance of nuclear export have not yet been elucidated. In addition, the existence and potential role of insulin-dependent regulation of Foxa2 have not been studied in other tissues where it is expressed, such as the gut, lung, and hypothalamus. Here we further investigate the regulation of Foxa2 by insulin and the mechanism and relevance of its nuclear exclusion. We demonstrate that differential regulation of Foxa2 exists in different mouse models, that this variability is dependent on circulating insulin levels, and that Foxa2 activity correlates with metabolic function. We further show that Foxa2 contains a functional nuclear export signal and is excluded from the nucleus via a CRM1- dependent pathway in response to insulin signaling. Our data provide direct evidence that nuclear export-defective Foxa2 is phosphorylated and inactivated by insulin both in vitro and in vivo, suggesting that phosphorylation itself is the main regulatory event regulating the activity of Foxa2, and not nuclear exclusion per se. Finally, we provide evidence for and physiological consequences of insulin-dependent inactivation of Foxa2 in two other metabolic organs: the hypothalamus and the lung.


A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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