Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2012 Jun;18(6):918-25. doi: 10.1038/nm.2757.
Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.
促进棕色脂肪组织 (BAT) 的形成和功能可能有助于减少肥胖。最近的数据表明视黄醛与能量平衡有关，但视黄醛代谢在白色脂肪和棕色脂肪中的具体作用尚不清楚。视黄醛脱氢酶 (Aldh)，也称为醛脱氢酶，是限速酶，可将视黄醛 (Rald) 转化为维甲酸。在这里，我们表明 Aldh1a1 主要在白色脂肪组织 (WAT) 中表达，包括小鼠和人类的内脏脂肪。Aldh1a1 基因缺失会在 WAT 中诱导出类似于 BAT 的转录程序，从而驱动解偶联呼吸和适应性产热。WAT 选择性的 Aldh1a1 敲低在肥胖小鼠中赋予了这种 BAT 程序，限制了体重增加并改善了葡萄糖稳态。Rald 通过选择性激活视黄酸受体 (RAR)、募集共激活因子 PGC-1α 和诱导 Ucp1 启动子活性，在白色脂肪细胞中诱导解偶联蛋白 1 (Ucp1) mRNA 和蛋白水平。这些数据确立了 Aldh1a1 及其底物 Rald 作为脂肪细胞可塑性和适应性产热的先前未被识别的决定因素，这可能具有潜在的治疗意义。
