Body fat reduction without cardiovascular changes in mice after oral treatment with the MAO inhibitor phenelzine

Christian Carpéné, Josep Mercader, Sophie Le Gonidec, Stéphane Schaak, Jeanne Mialet‐Perez, Alexia Zakaroff‐Girard, Jean Galitzky

Phenelzine is an antidepressant drug increasing the risk of hypertensive crisis when dietary tyramine is not restricted. However, this monoamine oxidase (MAO) inhibitor is known to inhibit other enzymes not limited to the nervous system. We studied whether its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to a mitigation of fattening without unwanted hypertensive or cardiovascular effects. Mice were fed a standard chow and subjected to a 0.028 % phenelzine drinking solution for 12 weeks. Body composition was determined by nuclear magnetic resonance. Cardiovascular dysfunction was assessed by heart rate variability (HRV) analyses and by evaluation of cardiac oxidative stress markers. MAO activity, hydrogen peroxide release, and triacylglycerol turnover were assayed in white adipose tissue (WAT), alongside determination of glucose and lipid circulating levels. Phenelzine-treated mice exhibited lower body fat content, subcutaneous WAT mass and lipid content in skeletal muscles than control, without decreased body weight gain or food consumption. A modest alteration of cardiac sympathovagal balance occurred without depressed aconitase activity. In WAT, phenelzine impaired insulin's lipogenic but not antilipolytic action, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non-fasting blood glucose and PEPCK expression. In vitro, high doses of phenelzine hampered both lipolytic and lipogenic responses in mouse adipocytes. Since phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of interest for the treatment of obesity-associated complications at the expense of the precautions of use recommended for antidepressant therapy.