Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora–derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

肥胖会导致多种健康问题，包括糖尿病、脂肪肝，甚至癌症。在此，我们报道尿石素 A (UA) 是一种石榴鞣花单宁 (ET) 的肠道微生物衍生代谢物，可预防小鼠饮食引起的肥胖和代谢功能障碍，且不会造成不良影响。UA 治疗通过增强棕色脂肪组织 (BAT) 的生热作用并诱导白色脂肪组织 (WAT) 褐变来增加能量消耗 (EE)。从机制上讲，UA 介导的生热作用增加是由 BAT 和腹股沟脂肪库中三碘甲状腺原氨酸 (T3) 水平升高引起的。这也在 UA 处理的白色和棕色脂肪细胞中得到证实。与这一机制一致，当甲状腺激素 (TH) 的产生被其抑制剂丙硫氧嘧啶 (PTU) 阻断时，UA 就会失去其对 BAT 激活、白色脂肪褐变、体重控制和葡萄糖稳态的有益作用。相反，给 PTU 处理的小鼠施用外源性四碘甲状腺原氨酸 (T4) 可以恢复 UA 诱导的 BAT 激活和白色脂肪褐变及其对高脂饮食 (HFD) 诱导的体重增加的预防作用。总之，这些结果表明 UA 是一种有效的抗肥胖剂，具有人类临床应用的潜力。