Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice

Abstract

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.

Attenuation of Weight Gain and Prevention of Associated Pathologies by Inhibiting SSAO

“…Phenelzine, which is a derivative of hydrazine, is found to affect adiposity, glucose, insulin, and lipid homeostasis as well as markers of oxidative stress and low-grade inflammation in mice models. It represents a potent inhibitor of MAO and SSAO [40,46,47]. Holoamine 2-bromoethylamine (2-BEA) was also discovered to be a highly selective potential inhibitor of membrane-bound SSAO [30].…”

“…Thus, inhibiting SSAO reduces the risks of the complications caused by SSAO-mediated deamination products such as formaldehyde and hydrogen peroxide [52]. Remarkably, SSAO inhibition diminishes excessive fat deposition, thus, it ameliorates low-grade inflammation and reduces oxidative stress, which, on the other hand, prevents further complications [46,47].…”

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

“…We extended a similar approach to the atypical anxiolytic and antidepressant drugs opipramol (Ensidon) and phenelzine (Nardil) by performing lipolysis assays on other sets of adipocyte preparations. Our working hypothesis was that opipramol, which is an iminostilbene derivative, would not exhibit any deleterious effect on lipolysis because it is not recognized for causing weight gain in patients [23], and that phenelzine could be potentially lipolytic because we recently reported that this MAO inhibitor limits fat accumulation in rodents [8,9,25], a finding observed with selegiline, another MAO inhibitor [26].…”

“…Nevertheless, numerous reports have indicated that various psychoactive agents are capable of directly modulate lipid accumulation in fat cells during short-term in vitro experiments. This is the case, but in the opposite sense, for an antidepressant drug, phenelzine, which inhibits insulin-induced lipogenesis in fat cells in less than an hour [6], impairs adipogenesis in cultured cells in the range of several days [7], and limits fat deposition in rodents chronically treated for weeks [8,9]. Indeed, the demonstration of a direct effect of a given psychoactive drug on adipocytes does not prevent the molecule to act in a concerted manner on gene regulation, and elsewhere on other cell types (and vice versa).…”

“…Alongside the test of their lipolytic and antilipolytic capacities on freshly isolated adipocytes, we also studied their putative interactions with the amine oxidases expressed in adipocytes. Exploring the effects on monoamine oxidase (MAO) was driven by the similarities between the adipose (mainly of the A form in human adipocytes [24]) and the brain forms, well known to be the target of a class of antidepressants, the MAO inhibitors, which have been recently reported to mitigate excessive fat deposition in rodents [8,9,25,26]. Thus, pargyline, phenelzine, and harmine were used as representatives of MAO inhibitors in both assays of lipolytic or amine oxidation activities.…”