The Antidepressant Phenelzine Alters Differentiation of Cultured Human and Mouse Preadipocytes

Change in body weight is a frequent side effect of antidepressants, and is considered to be mediated by central effects on food intake and energy expenditure. The antidepressant phenelzine (NARDIL) potently inhibits both monoamine oxidase and semicarbazide-sensitive amine oxidase activities, two enzymes that are highly expressed in adipose tissue, raising the possibility that it could directly alter adipocyte biology. Treatment with this compound is rather associated with weight gain. The aim of this work was to examine the effects of phenelzine on differentiation and metabolism of cultured human and mouse preadipocytes, and to characterize the mechanisms involved in these effects. In all preadipocyte models, phenelzine induced a timeand dose-dependent reduction in differentiation and triglyceride accumulation. Modulation of lipolysis or glucose transport were not involved in phenelzine action. This effect was supported by the reduced expression in the key adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein-alpha (C/EBP-alpha), which was observed only at the highest drug concentrations (30-100 μM). The PPAR-gamma agonists thiazolidinediones did not reverse phenelzine effects. By contrast both the reduction in cell triglycerides and in sterol regulatory elementbinding protein-1c (SREBP-1c) was detectable at lower phenelzine concentrations (1-10 μM). Phenelzine effect on triglyceride content was prevented by providing free fatty acids to the cells, and was partially reversed by overexpression of a dominant positive form of SREBP-1c, showing the privileged targeting of the lipogenic pathway. When considered together, these findings demonstrate that an antidepressant directly and potently inhibits adipocyte lipid storage and differentiation, that could contribute to psychotropic drug side effects on energy homeostasis. This article has not been copyedited and formatted. The final version may differ from this version. Molecular Pharmacology Fast Forward. Published on February 6, 2009 as DOI: 10.1124/mol.108.052563 at A PE T Jornals on Jne 2, 2017 m oharm .aspeurnals.org D ow nladed from