Analyzing the role of a truncated Adenylyl Cyclase 3 isoform in brown adipose tissue

Abstract

Obesity has become one of the main public health issues in the 21^st century. Targeting brown adipose tissue (BAT) activity, which is physiologically induced by cold temperatures, has been recognized as a potential therapeutic approach to tackle the obesity epidemic. Whereas the main molecular players of BAT activation have been identified, their precise regulation through, e.g., epigenetic modification, is not well understood. Recently, it was found that cold exposure leads to the formation of novel H3K4me3 sites in the <em>adenylyl cyclase 3</em> gene. In <em>Adcy3</em>, the H3K4me3 domain arising from cold induction marks a novel transcription start site, which gives rise to a 5’ truncated alternate transcript (AT), termed <em>Adcy3-at</em>. However, the function of AC3-AT in BAT is unknown. Here, I demonstrate that AC3-FL, but not AC3-AT, localizes to the plasma membrane, suggesting that AC3-AT is retained in the endoplasmic reticulum. I also found that AC3-AT itself is catalytically inactive. I could demonstrate that AC3-AT heterodimerizes with AC3-FL. Moreover, I found that AC3-AT impairs the transport of AC3-FL to the plasma membrane, which reduces AC3-FL levels in the plasma membrane, resulting in lower cAMP production in the cell. In summary, my results indicate that the expression of truncated AC protein isoforms provides a mechanism to regulate intracellular cAMP signaling in brown adipocytes. I anticipate my research to be a starting point for more sophisticated pharmacological approaches to activate BAT and thereby tackle the obesity epidemic.