Tyramine exerts hypolipidemic and anti-obesity effects in vivo

Abstract Obesity and dyslipidemia are conditions often associated with cardiovascular risk, inflammation, oxidative stress, and death. Thus, a new approach has been highlighted to promote research and development of pharmacological tools derived from natural sources. Among the most widely studied groups of substances, polyphenols such as tyramine stand out. This study investigated hypolipidemic and anti-obesity properties of tyramine. Oral toxicity evaluation, models of dyslipidemia and obesity were used. To induce dyslipidemia, Poloxamer-407 (P-407) was administered intraperitoneally. In the hypercholesterolemic and obesity model, specific diet and oral tyramine were provided. After 24h of P-407 administration, tyramine 2 mg/kg (T2) decreased triglycerides (TG) (2057.0 ± 158.5 mg/dL vs. 2838 ± 168.3 mg/dL). After 48h, TG were decreased by T2 (453.0 ± 35.47 vs. 760.2 ± 41.86 mg/dL) and 4 mg/kg (T4) (605.8 ± 26.61 760.2 ± 41.86 mg/dL). T2 reduced total cholesterol (TC) after 24h (309.0 ± 11.17 mg/dL vs. 399.7 ± 15.7 mg/dL); After 48h, 1 mg/kg (T1) (220.5 ± 12.78 mg/dL), T2 (205.8 ± 7.1 mg/dL) and T4 (216.8 ± 12.79 mg/dL), compared to P-407 (275.5 ± 12.1 mg/dL). The treatment decreased thiobarbituric acid reactive substances and nitrite in liver, increased superoxide dismutase, reduced the diet-induced dyslipidemia, decreasing TC around 15%. Tyramine reduced body mass, glucose, and TC after hypercaloric feed. Treatment with 5 mg/L (0.46 ± 0.04 ng/dL) and 10 mg/L (0.44 ± 0.02 ng/dL) reduced plasma insulin (1.18 ± 0.23 ng/dL). Tyramine increased adiponectin at 5 mg/L (1.02 ± 0.02 vs. 0.83 ± 0.02 ng/mL) and 10mg/L (0.96 ± 0.04 ng/mL). In conclusion, tyramine has low toxicity in rodents, has antioxidant effect, reduces plasma triglycerides and cholesterol levels. However, further studies should be conducted in rodents and non-rodents to better understand the pharmacodynamic and pharmacokinetic properties of tyramine.

摘要：肥胖与血脂异常是常与心血管风险、炎症、氧化应激及死亡相关的病症。为此，研发源自天然产物的药理学干预手段的全新研究方向受到广泛关注。在被广泛研究的物质类别中，多酚类（polyphenols）物质如酪胺（tyramine）尤为引人注目。本研究探究了酪胺的调脂与抗肥胖活性。研究采用了口服毒性评价方法以及血脂异常与肥胖模型。为诱导血脂异常模型，研究者通过腹腔注射给予泊洛沙姆-407（Poloxamer-407，P-407）；在高胆固醇血症合并肥胖模型中，受试动物被给予特制饲料与口服酪胺。给予P-407 24小时后，2mg/kg剂量酪胺（T2组）可降低甘油三酯（triglycerides，TG）水平（2057.0±158.5mg/dL vs. 2838±168.3mg/dL）。给药48小时后，T2组（453.0±35.47 vs. 760.2±41.86mg/dL）与4mg/kg剂量酪胺组（T4组，605.8±26.61 vs. 760.2±41.86mg/dL）均能降低TG水平。T2组在给药24小时后可降低总胆固醇（total cholesterol，TC）水平（309.0±11.17mg/dL vs. 399.7±15.7mg/dL）；给药48小时后，1mg/kg剂量组（T1组，220.5±12.78mg/dL）、T2组（205.8±7.1mg/dL）与T4组（216.8±12.79mg/dL）的TC水平均低于P-407模型组（275.5±12.1mg/dL）。酪胺处理可降低肝脏组织中硫代巴比妥酸反应物质与亚硝酸盐水平，提升超氧化物歧化酶（superoxide dismutase）活性，缓解饲料诱导的血脂异常，使总胆固醇水平降低约15%。在给予高热量饲料后，酪胺可降低受试动物体质量、血糖与总胆固醇水平。以5mg/L与10mg/L剂量的酪胺处理，可降低血浆胰岛素水平（对照组为1.18±0.23ng/dL，处理组分别为0.46±0.04ng/dL与0.44±0.02ng/dL）。5mg/L剂量组（1.02±0.02 vs. 0.83±0.02ng/mL）与10mg/L剂量组（0.96±0.04ng/mL）的酪胺处理可提升脂联素（adiponectin）水平。综上，酪胺对啮齿类动物毒性较低，具备抗氧化活性，可降低血浆甘油三酯与胆固醇水平。但未来仍需在啮齿类与非啮齿类动物中开展进一步研究，以更全面地阐明酪胺的药效学（pharmacodynamic）与药代动力学（pharmacokinetic）特性。