Chiche Françoise, Le Guillou Morwenna, Chétrite Gérard, Lasnier Françoise, Dugail Isabelle, Carpéné Christian, Moldes Marthe, Fève Bruno
Institut National de la Santé et de la Recherche Médicale U693, University Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.
Mol Pharmacol. 2009 May;75(5):1052-61. doi: 10.1124/mol.108.052563. Epub 2009 Feb 6.
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.
体重变化是抗抑郁药常见的副作用，被认为是由对食物摄入和能量消耗的中枢作用介导的。抗抑郁药苯乙肼（Nardil）能有效抑制单胺氧化酶和氨基脲敏感性胺氧化酶的活性，这两种酶在脂肪组织中高度表达，这增加了它可能直接改变脂肪细胞生物学特性的可能性。然而，用这种化合物治疗却与体重增加有关。这项研究的目的是研究苯乙肼对培养的人和小鼠前脂肪细胞分化和代谢的影响，并确定这些影响所涉及的机制。在所有前脂肪细胞模型中，苯乙肼诱导分化和甘油三酯积累呈时间和剂量依赖性降低。苯乙肼的作用不涉及脂解或葡萄糖转运的调节。这种作用得到关键脂肪生成转录因子过氧化物酶体增殖物激活受体γ（PPAR-γ）和CCAAT/增强子结合蛋白α表达降低的支持，这种降低仅在最高药物浓度（30-100 microM）时观察到。PPAR-γ激动剂噻唑烷二酮类药物并不能逆转苯乙肼的作用。相比之下，在较低的苯乙肼浓度（1-10 microM）下就可检测到细胞甘油三酯和固醇调节元件结合蛋白-1c（SREBP-1c）的降低。通过向细胞提供游离脂肪酸可阻止苯乙肼对甘油三酯含量的影响，并且通过过表达显性阳性形式的SREBP-1c可部分逆转这种影响，这表明其对脂肪生成途径具有优先靶向作用。综合来看，这些发现表明一种抗抑郁药可直接且有效地抑制脂肪细胞脂质储存和分化，这可能导致精神药物对能量稳态产生副作用。
