The Regulation of Brown Adipose Tissue Activation by Multiple Phosphodiesterases

Brown adipose tissue is a highly thermogenic, energy "wasting" organ that converts glucose and lipids into heat. Many of the critical metabolic and gene transcriptional processes, such as uncoupling protein-1 (UCP1) mRNA expression, lipolysis and glucose uptake are regulated by the β-adrenergic receptor-dependent signaling cascade through the second messenger, adenosine-3',5'-cyclic monophosphate (cAMP). Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that catalyze the breakdown of cAMP, and thereby regulate the duration and magnitude of this signal. Yet, neither the types of PDEs that are expressed in BAT nor how they regulate the major processes that lead to thermogenesis have been well characterized.;In this dissertation, I present evidence that BAT activity is largely regulated by several different PDEs working in concert. In the basal state, it required a combination of PDE3 and PDE4 inhibitors to fully induce UCP1 mRNA expression and activate lipolysis in brown adipocytes, whereas neither inhibitor had any substantial effect when administered alone. Furthermore, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions. This response was further potentiated by the global ablation of PDE8A. On the other hand, when brown adipocytes were co-stimulated with a β-adrenergic agonist, a PDE3 inhibitor could potentiate UCP1 mRNA expression, but not lipolysis; whereas a PDE4 inhibitor could not potentiate UCP1 mRNA expression, but did potentiate lipolysis and cAMP accumulation. This suggests a differential role for these PDEs when β-adrenergic receptors are activated.;Due to its high metabolic inefficiency, BAT has been implicated as a potential therapeutic target for the treatment of obesity and its various comorbidities. It is thought that increasing the amount and/or the activity of brown fat could lead to increased energy expenditure and a decrease in body weight, a phenomenon that has been demonstrated in rodent models. However, selective pharmacological activation of brown adipose tissue in humans has remained elusive due to a lack of adipocyte-specific adrenergic receptors expressed on its surface. In light of this, new alternative approaches are required to translate this hypothesis to the clinic. Taken together, the results presented here provide a new conceptual basis for the development of therapeutics that activate BAT by selectively targeting a combination of PDEs.