红参提取物通过激活肠道 TGR5 介导的胆汁酸信号通路改善高脂饮食诱导的肥胖和胰岛素抵抗。
Red ginseng extracts ameliorate high-fat diet-induced obesity and insulin resistance by activating the intestinal TGR5-mediated bile acids signaling pathway.
机构信息
Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Department of Diabetes Complications and Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
出版信息
Phytomedicine. 2023 Oct;119:154982. doi: 10.1016/j.phymed.2023.154982. Epub 2023 Jul 22.
BACKGROUND
Obesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified.
PURPOSE
This study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements.
METHODS
The role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity.
RESULTS
RGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5 obese mice. Furthermore, RGS intervention increased BA levels in serum, ileum, and iWAT. The increase of circulating BAs in mice was related to the activation of ileal TGR5 and the promotion of ASBT translocation to the plasma membrane, thus affecting BA transport. Next, the increased level of circulating BAs entered the periphery, which might facilitate lipolysis and energy consumption by activating TGR5 in iWAT.
CONCLUSION
Our results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.
背景
肥胖症已成为一种全球性的代谢性疾病，其在全球的患病率迅速上升。红参提取物（RGS）是人参的传统加工产品之一，具有改善肥胖代谢表型的潜力。然而，RGS 调节肥胖和晚期胰岛素抵抗的机制仍需阐明。
目的
本研究旨在强调 RGS 在肥胖和胰岛素抵抗（IR）治疗中的潜在用途，并探讨影响改善葡萄糖和脂质代谢的潜在机制。
方法
在高脂肪饮食（HFD）啮齿动物模型中评估 RGS 的作用。进行葡萄糖耐量试验（GTT）和胰岛素耐量试验（ITT）以表征葡萄糖代谢水平。通过 Western blot 检测脂肪分解蛋白和解偶联蛋白-1（UCP-1）的表达。通过免疫荧光法测定肠道胰高血糖素样肽-1（GLP-1）和顶端钠依赖性胆汁酸转运体（ASBT）蛋白的表达。使用 UPLC-Q-TOF-MS 检测血清、回肠和腹股沟白色脂肪组织（iWAT）中胆汁酸（BAs）水平的变化。此外，还使用肠道特异性 Tgr5 敲除小鼠来验证 RGS 改善肥胖的功效。
结果
RGS 治疗以剂量依赖的方式减轻了肥胖小鼠饮食诱导的血脂异常和 IR，并改善了葡萄糖和胰岛素耐量以及能量消耗。RGS 治疗显著减少了野生型小鼠肠道中的脂质沉积并诱导 GLP-1 分泌，但在 Tgr5 肥胖小鼠中则没有。此外，RGS 干预增加了血清、回肠和 iWAT 中的 BA 水平。小鼠循环 BAs 的增加与回肠 TGR5 的激活和 ASBT 向质膜的易位有关，从而影响 BA 转运。接下来，进入外周的循环 BAs 可能通过激活 iWAT 中的 TGR5 来促进脂肪分解和能量消耗。
结论
我们的研究结果表明，RGS 可显著减轻 HFD 诱导的肥胖和胰岛素抵抗。RGS 干预通过激活肠道中的 TGR5 改善葡萄糖代谢，促进脂肪分解和能量代谢。此外，我们发现激活肠道 TGR5 促进了 ASBT 向质膜的定位，最终促进了 BAs 的转运以调节代谢表型。
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