Ni Xintao, Cheng Siyao, Jin Xiaoqin, Sun Yunxia, Yang Zhenggang, Hu Miaofen G, Hou Xiaoli
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; College of Basic Medical Sciences, Zhejiang Chinese Medical University, China.
Academy of Chinese Medical Science, Zhejiang Chinese Medical University, China.
J Ethnopharmacol. 2025 Jul 7;352:120266. doi: 10.1016/j.jep.2025.120266.
Gegen Huazhuo Tang (GHT), an empirical clinical prescription for treating hyperlipidemia in China, is composed of five herbs with both medicine and food uses and one functional food derived from traditional medicine, all of which exhibit hypolipidemic and anti-obesity effects. However, ingredients and pharmacological mechanism of GHT remains unexplored.
We investigated the role of GHT on high-fat diet (HFD)-induced obesity and its molecular regulation on adipose thermogenesis.
The ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify components of GHT and metabolites in GHT-containing serum (GHTS) from GHT-treated rats. In vivo, six-week-old male C57BL/6J mice were randomly assigned to control (distilled water) and GHT (13 g/kg/day via gavage) groups fed either a normal chow diet (NCD) or HFD for 12 weeks. In vitro, adipocytes differentiated from inguinal white adipose tissue (iWAT)-isolated stromal vascular fraction (SVF) cells and 3T3-L1 preadipocytes were used to evaluate the effect of GHTS metabolites on thermogenesis.
Thirteen chemical components were identified in GHT and eleven differential metabolites were confirmed in GHTS. GHT prevented obesity through increasing white fat browning via the parallel recruitment of UCP1-dependent and UCP1-independent (sarco/endoplasmic reticulum Ca-ATPase 1, SERCA1 and mitochondrial creatine kinase 2, CKMT2) systems. GHT reduced serum 7-ketodeoxycholic acid (7-KDCA) levels, thereby activating adipose Takeda G protein-coupled receptor 5 (TGR5) and downstream AMPK signaling pathways to promote thermogenic beige adipocyte formation. Correspondingly, following the addition of 7-KDCA, the expressions of UCP1-dependent and UCP1-independent browning markers in mature adipocytes were inhibited via suppressing TGR5-AMPK.
These findings demonstrate that GHT reduces serum 7-KDCA and consequently activates TGR5-AMPK signaling to induce UCP1-dependent and UCP1-independent thermogenesis in white adipose tissue and protect against obesity.
葛根化浊汤（GHT）是中国用于治疗高脂血症的经验性临床处方，由五种药食两用的草药和一种源自传统医学的功能性食品组成，所有这些成分均具有降血脂和抗肥胖作用。然而，GHT的成分和药理机制仍未得到探索。
我们研究了GHT对高脂饮食（HFD）诱导的肥胖的作用及其对脂肪产热的分子调节作用。
采用超高效液相色谱-四极杆飞行时间质谱联用技术（UPLC-Q/TOF-MS）鉴定GHT的成分以及GHT处理大鼠含药血清（GHTS）中的代谢产物。在体内，将六周龄雄性C57BL/6J小鼠随机分为对照组（蒸馏水）和GHT组（通过灌胃给予13 g/kg/天），分别给予正常饲料（NCD）或HFD喂养12周。在体外，使用从腹股沟白色脂肪组织（iWAT）分离的基质血管成分（SVF）细胞和3T3-L1前脂肪细胞分化而来的脂肪细胞来评估GHTS代谢产物对产热的影响。
在GHT中鉴定出13种化学成分，在GHTS中确认了11种差异代谢产物。GHT通过平行募集UCP1依赖性和UCP1非依赖性（肌浆网/内质网Ca-ATP酶1，SERCA1和线粒体肌酸激酶2，CKMT2）系统增加白色脂肪褐变，从而预防肥胖。GHT降低血清7-酮脱氧胆酸（7-KDCA）水平，从而激活脂肪组织中的武田G蛋白偶联受体5（TGR5）和下游AMPK信号通路，促进产热米色脂肪细胞的形成。相应地，添加7-KDCA后，通过抑制TGR5-AMPK抑制成熟脂肪细胞中UCP1依赖性和UCP1非依赖性褐变标记物的表达。
这些发现表明，GHT可降低血清7-KDCA水平，从而激活TGR5-AMPK信号，诱导白色脂肪组织中UCP1依赖性和UCP1非依赖性产热，预防肥胖。
