Balearic Islands Health Research Institute, Palma de Mallorca, Spain (J.M.); Department of Fundamental Biology and Health Sciences, University of Balearic Islands (UIB), Palma de Mallorca, Spain (J.M.); Alimentómica, S.L., Spin-off from UIB, Palma de Mallorca, Spain (A.G.S.); Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Teams 1 & 3, Toulouse, France (C.C., S.L.G., P.D.); I2MC, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse Cedex 4, France (C.C., S.L.G., P.D.); Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, Ohio (A.C.); Nutrition and Obesity Group, Department of Nutrition and Food Science, University of the Basque Country and Lucio Lascaray Research Institute, Vitoria, Spain (S.G.-Z.); CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain (S.G.-Z., F.I.M.); Department of Nutrition, Food Science, and Physiology, University of Navarra, Pamplona, Spain (F.I.M.); and Centre for Nutrition Research, University of Navarra, Pamplona, Spain (F.I.M.)
Balearic Islands Health Research Institute, Palma de Mallorca, Spain (J.M.); Department of Fundamental Biology and Health Sciences, University of Balearic Islands (UIB), Palma de Mallorca, Spain (J.M.); Alimentómica, S.L., Spin-off from UIB, Palma de Mallorca, Spain (A.G.S.); Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Teams 1 & 3, Toulouse, France (C.C., S.L.G., P.D.); I2MC, University of Toulouse, UMR1048, Paul Sabatier University, Toulouse Cedex 4, France (C.C., S.L.G., P.D.); Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, Ohio (A.C.); Nutrition and Obesity Group, Department of Nutrition and Food Science, University of the Basque Country and Lucio Lascaray Research Institute, Vitoria, Spain (S.G.-Z.); CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain (S.G.-Z., F.I.M.); Department of Nutrition, Food Science, and Physiology, University of Navarra, Pamplona, Spain (F.I.M.); and Centre for Nutrition Research, University of Navarra, Pamplona, Spain (F.I.M.).
J Pharmacol Exp Ther. 2019 Nov;371(2):555-566. doi: 10.1124/jpet.119.259895. Epub 2019 Jul 3.
Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT: Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.
新型机制和健康益处最近被提出用于抗抑郁药苯乙肼（PHE），它被认为是一种非选择性单胺氧化酶抑制剂。它们包括一种抗脂肪生成作用，可能对过度脂肪积累和肥胖相关的代谢改变产生影响。我们评估了口服 PHE 治疗对高脂肪饮食（HFD）喂养的小鼠的代谢影响。11 周龄雄性 C57BL/6 小鼠喂食 HFD，并饮用 0.028%的 PHE 溶液（HFD+PHE）或水，持续 11 周。PHE 减轻了体重和肥胖的增加，而不影响食物的摄入。HFD+PHE 小鼠的能量效率较低。皮下脂肪垫、肝脏和骨骼肌中的脂质含量减少。在白色脂肪组织（WAT）中，PHE 降低了固醇调节元件结合蛋白-1c 和磷酸烯醇丙酮酸羧激酶的 mRNA 水平，抑制了胺诱导的脂肪生成，并且没有增加脂肪分解。此外，HFD+PHE 小鼠的皮下 WAT 中释放的过氧化氢水平降低，内脏 WAT 和肝脏中的白细胞迁移标志物和促炎细胞因子的表达减少。PHE 降低了循环中的甘油、三酰基甘油、高密度脂蛋白胆固醇和胰岛素水平。胰岛素抵抗降低，而不影响血糖水平和葡萄糖耐量。相反，PHE 增加了直肠温度，略微增加了能量消耗。减轻 HFD 引起的代谢紊乱表明 PHE 在肥胖治疗中具有有希望的作用，并鼓励对其作用机制进行进一步的研究。意义：苯乙肼可减少高脂肪饮食小鼠的体脂肪、氧化应激、炎症和胰岛素抵抗标志物。半卡巴嗪敏感胺氧化酶、单胺氧化酶、磷酸烯醇丙酮酸羧激酶和固醇调节元件结合蛋白-1c 参与了苯乙肼的代谢作用。苯乙肼可能可用于治疗肥胖相关并发症。
