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

Background and Purpose Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits other enzymes not limited to the nervous system. Here we investigated if its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to decreased body fat in vivo , without unwanted hypertensive or cardiovascular effects. Experimental Approach Mice were fed a standard chow and given 0.028% phenelzine in drinking water for 12 weeks. Body composition was determined by NMR. Cardiovascular dysfunction was assessed by heart rate variability 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. Key Results 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 the lipogenic but not the antilipolytic actions of insulin, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non‐fasting blood glucose and phosphoenolpyruvate carboxykinase expression. In vitro , high doses of phenelzine decreased both lipolytic and lipogenic responses in mouse adipocytes. Conclusion and Implications As phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of benefit in the treatment of obesity‐associated complications, with the precautions of use recommended for antidepressant therapy.