Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function

Abstract

Promoting brown adipose tissue (BAT) activity innovatively targetsobesity and metabolic disease. While thermogenic activation of BAT is wellunderstood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase3 (AC3) is key for BAT function. We identified a cold-inducible promoter thatgenerates a 5′ truncated AC3 mRNA isoform (<em>Adcy3-at</em>), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT).Male mice lacking <em>Adcy3-at</em> display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.