Regulation and adaption of adenylyl cyclases and cAMP signaling networks in brown and beige adipose tissue

Abstract

β-adrenergic stimulation of brown adipose tissue (BAT) via G-protein coupled receptors (GPCRs) promotes BAT activity by increasing cellular cAMP levels through activating adenylyl cyclase 3 (AC3). We recently demonstrated that upon cold exposure, BAT expresses a truncated AC3 isoform (AC3-AT). Loss of <em>Adcy3-at</em> increases energy expenditure and protects from obesity and ensuing metabolic imbalances. I revealed that AC3-AT is retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and in turn interacts and sequesters AC3, thereby limiting cAMP synthesis. Thus, these findings reveal that AC3-AT acts as a cold-induced rheostat in BAT, limiting cAMP synthesis during chronic BAT activation. To preserve brown adipocyte function and tissue homeostasis, it is crucial to maintain a pool of adipocyte progenitor cells (APCs), which differentiate into mature brown adipocytes. Two distinct APC subpopulations in BAT are platelet-derived growth factor receptor α (PDGFRA)-expressing cells and highly thermogenic transient-receptor potential (TRP) vanilloid 1 (TRPV1) APCs derived from vascular smooth muscle (VSM) cells. One subcellular compartment, enriched with a unique receptor repertoire that has been proposed to play a key role during APC differentiation is the primary cilium. Increasing ciliary cAMP levels, has been shown to promote APC differentiation. Notably, AC3 is predominantly localized in primary cilia of APCs. However, how AC3 regulates ciliary cAMP signaling in brown APCs to control proliferation and differentiation is not known. I demonstrated that loss of AC3 in brown APCs reduces ciliary cAMP synthesis and in turn subpopulation expansion and differentiation. Furthermore, loss of AC3 in highly thermogenic APCs reduced BAT activity during an acute cold stimulus. In contrast increased ciliary AC3 abundance promoted expansion of brown APCs in BAT after cold exposure. My results reveal that AC3-mediated ciliary cAMP signaling is controlling brown APC differentiation and function and, therefore, a crucial regulator of BAT homeostasis. The ciliary dysfunction Bardet-Biedl syndrome (BBS) caused by mutations in one of the BBS genes leads to severe obesity and altered ciliary GPCR composition. Loss of BBS proteins has been associated with impaired thermogenesis and lipid metabolism, and on a cellular level a fate switch to a more fibrogenic phenotype in white APCs. However, whether BBS affects the function of brown APCs is not known. I demonstrated that loss of BBS8 reduces ciliary AC3 abundance in brown APCs and in turn subpopulation expansion and differentiation in BAT. These results reveal that BBS affects ciliary cAMP signaling in brown APCs and thereby alters subpopulation abundance and adipogenesis, and potentially BAT function.