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 time- and dose-dependent reduction in differentiation and triglyceride accumulation. Modulation of lipolysis or glucose transport was 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, which was observed only at the highest drug concentrations (30-100 microM). The PPAR-gamma agonists thiazolidinediones did not reverse phenelzine effects. By contrast, the reduction in both cell triglycerides and sterol regulatory element-binding protein-1c (SREBP-1c) was detectable at lower phenelzine concentrations (1-10 microM). 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, which could contribute to psychotropic drug side effects on energy homeostasis.
Chiche
Françoise
F
Institut National de la Santé et de la Recherche Médicale U693, University Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.
Le Guillou
Morwenna
M
Chétrite
Gérard
G
Lasnier
Françoise
F
Dugail
Isabelle
I
Carpéné
Christian
C
Moldes
Marthe
M
Fève
Bruno
B
D016475:3T3 Cells; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D047495:PPAR gamma / Q000502:physiology; D010624:Phenelzine / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
D000928:Antidepressive Agents; D008996:Monoamine Oxidase Inhibitors; D047495:PPAR gamma; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D010624:Phenelzine