Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at 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.

促进棕色脂肪组织 (BAT) 活性以创新方式针对肥胖和代谢疾病。虽然 BAT 的生热激活已被充分了解，但 BAT 的变阻调节以避免过度能量耗散仍然不明确。在这里，我们证明腺苷酸环化酶 3 (AC3) 是 BAT 功能的关键。我们鉴定了一个冷诱导启动子，它产生 5' 截短的 AC3 mRNA 亚型 ( Adcy3-at )，其表达由冷诱导的 PPARGC1A 截短亚型 (PPARGC1A-AT) 驱动。缺乏Adcy3-at的雄性小鼠表现出能量消耗增加，并且能够抵抗肥胖和随之而来的代谢失衡。小鼠和人类 AC3-AT 保留在内质网中，无法转位至质膜并且缺乏酶活性。 AC3-AT 与 AC3 相互作用，并将其隔离在内质网中，从而减少可用于 G 蛋白介导的 cAMP 合成的腺苷酸环化酶库。因此，AC3-AT 在 BAT 中充当冷诱导变阻器，限制 BAT 慢性激活期间 cAMP 活性的不利后果。