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.
Highlights
Phenelzine is a drug prescribed for atypical depression, bipolar depression, and major depressive disorder that is resistant to other antidepressant drugs
We have recently shown that chronic phenelzine administration reduces body fat accumulation even in normal-weight mice, which was associated to a lower rate of insulin- and benzylamine-stimulated glucose incorporation into lipids in adipocytes [12]
At the end of the treatment, the weights of liver, inguinal white adipose tissue, and interscapular brown adipose tissue pads were heavier in sucrose-drinking mice (SUC) versus control water-drinking mice (CON) mice, when expressed as percentage of body weight
Summary
Phenelzine is a drug prescribed for atypical depression, bipolar depression, and major depressive disorder that is resistant to other antidepressant drugs. Insulin-stimulated de novo lipogenesis is inhibited by phenelzine [9], indicating that mechanisms other than amine oxidase inhibition are involved in its antilipogenic effect Another mechanism by which phenelzine inhibits the assembly of triacylglycerides is by targeting sterol regulatory element-binding protein-1c (SREBP-1c) in differentiating adipocytes. Such an effect eventually inhibits adipocyte differentiation, which has been shown in several murine cell lines and in human primary cultures of a stromal vascular fraction derived from adipose tissue and bone marrow mesenchymal stem cells [10,11]. We recently described that body fat reduction was achieved without cardiovascular changes [12], reinforcing the potential benefit of phenelzine against obesity
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