Adenosine Regulation of Adipose Tissue Lipid Metabolism
Granade, Mitchell, Pharmacology - School of Medicine, University of Virginia
Harris, Thurl, MD-PHAR Pharmacology, University of Virginia
Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. During feeding, adipose tissue acts as a physiological buffer for excess energy through lipid storage, while adipocyte lipolysis provides the body with a necessary source of energy through fatty acids during fasting. The dysregulation of these processes contributes to the development of metabolic syndrome and type 2 diabetes, so it is essential that we understand the pathways which regulate adipose tissue metabolism. Adenosine has been well characterized as an important regulator of adipocyte metabolism, and alterations in adenosine signaling are associated with obesity and metabolic syndrome. In this dissertation, we explore the regulation of adipose tissue metabolism by adenosine and its impacts on whole-body metabolic homeostasis. Adipose tissue is believed to be regulated by adenosine primarily through its actions on A1 adenosine receptors (A1R), and we find that A1R augments insulin action in adipocytes and opposes catecholaminergic stimulation of adipocyte lipolysis in vivo. We also found that adenosine signaling in adipose tissue is not static but is dynamically shifted between fasting and feeding through transcriptional control of A1R and A2B adenosine receptors. This shift in adenosine signaling may enable adipocytes to be more responsive to changing nutrient conditions.
PHD (Doctor of Philosophy)
adipose, lipolysis, adenosine, adenosine receptors, Adora1, Adora2B, FOXO1, obesity, A1, A2B