TY - JOUR T1 - Oral Phenelzine Treatment Mitigates Metabolic Disturbances in Mice Fed a High-Fat Diet JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.259895 SP - jpet.119.259895 AU - JOSEP Mercader AU - Agustin Sabater AU - Sophie Le Gonidec AU - Pauline Decaunes AU - Alice Chaplin AU - Saioa Gomez-Zorita AU - Fermin Milagro AU - Christian Carpene Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/07/03/jpet.119.259895.abstract N2 - Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine, known as a non-selective MAO inhibitor. They include an anti-lipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral phenelzine 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% phenelzine solution (HFD+PHE) or water to drink for 11 weeks. Phenelzine 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), phenelzine 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 pro-inflammatory cytokines in visceral WAT and liver. Phenelzine reduced the circulating levels of glycerol, triacylglycerols, HDL-cholesterol and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. On the other hand, phenelzine increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points towards a promising role for phenelzine 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 HFD mice. SSAO, MAO, PEPCK and SREBP1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications. ER -