Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting β-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic beige fat, a subpopulation of beige adipocytes mediated by GABPα emerging in the absence of β-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in beige fat biogenesis and energy homeostasis.

在环境挑战（例如寒冷或摄入过多的卡路里）下保持能量稳态对哺乳动物的健康和生存至关重要。经过数十年的深入研究，针对β-肾上腺素信号传导的药物发现工作并未取得成果。我们最近发现了通过烟碱乙酰胆碱受体亚基CHRNA2介导的新的米色脂肪调节途径。在这里，我们生成了脂肪特异性的Chrna 2 KO小鼠，并观察到由体内脂肪细胞自主调节引起的饮食挑战引起的感冒和代谢功能障碍的致热缺陷。我们发现，在急性高脂饮食喂养后，CHRNA2信号被激活，这种作用通过UCP1和肌酸介导的机制得以体现。此外，我们的数据表明，CHRNA2信号传导可能激活糖酵解米色脂肪，这是由GABPα介导的米色脂肪细胞的亚群，在没有β-肾上腺素信号传导的情况下出现。这些发现揭示了CHRNA2途径在米色脂肪的生物发生和能量稳态中的生物学意义。