Akt Regulation of Adipogenesis: Implications for Skp2 Involvement

Amongst the backdrop of a worldwide obesity epidemic and its increased risk for heart disease, diabetes, stroke, and a wide range of cancers, including breast, colon, uterus and prostate, there has been mounting interest in the study of adipose tissue and adipocytes, including how adipocytes are formed, a process called adipogenesis and their physiological interactions at the systemic level. Adipose is an insulin responsive tissue that has been shown to play an important role in promoting and maintaining energy balance and insulin sensitivity. Akt has been shown to be important for adipogenesis as Akt2 deficient mice as well humans with a dominant negative mutation in Akt2 are lipodystrophic and severely insulin resistant. In line with its ability to promote cell survival, inhibit apoptosis and regulate cell metabolism and cell cycle progression, the Insulin-PI3K-Akt pathway also tends to be hyperactivated in a majority of tumors. In this PhD work, we elucidated the regulation of a specific target of the PI3K-Akt pathway, Skp2 and its role in the formation of both White adipose tissue (WAT) and brown adipose tissue (BAT) as well as a process important to tumorigenesis, escape from contact inhibition. We examined the role of Akt in adipocyte functionality in both mouse and human systems of adipogenesis and found that Akt is important for Glut4, adiponectin and leptin expression, all of which are mediators of glucose homeostasis. Insights from these studies can help us develop strategies to prevent and/or combat obesity. In addition, as Skp2 is overexpressed in many recurrent and chemoresistant tumors, we further show that the regulation of Skp2 by Akt to be important for cells to escape contact inhibition, a hallmark feature of tumor cells. We found in both adipogenesis and regulation of cell cycle progression by Akt was mediated by an upregulation of Skp2 at the translational level and not at the transcriptional level or through protein stability. Thus, understanding the regulation of this protein can also confer insights into translational targets in cancer therapy and potential side effects of inhibiting Akt on adipocyte function and glucose homeostasis.