The Antidepressant Trans-2-Phenylcyclopropylamine Protects Mice from High-Fat-Diet-Induced Obesity

Abstract

Mice treated with the antidepressant trans-2-phenylcyclopropylamine (2-PCPA) were protected against diet-induced-obesity, and adiposity was reversed in pre-established diet-induced obese mice. Contrary to a recent report that inhibition of lysine-specific demethylase-1 by 2-PCPA results in increased energy expenditure, long-term 2-PCPA treatment had no such effect but its protection against obesity was associated with increased spontaneous locomotor activity, Moreover, pair feeding to assure equal caloric intake in wild type mice as well as in genetic hyperphagic mice (ob/ob) also resulted in weight reduction in 2-PCPA treated mice that correlated with increased activity but no change in energy expenditure. Similarly, short-term intraperitoneal injections of 2-PCPA did not affect food intake but caused a substantial increase in locomotor activity in the light cycle that correlated with increased energy expenditure, whereas activity and energy expenditure were unchanged in the dark cycle. Lastly, 2-PCPA was also effective in reducing obesity in genetic UCP1 null mice. These data suggest that 2-PCPA can reduce obesity by decreasing food intake in the long term while increasing activity in the short-term. However, the protective and weight loss effects of 2-PCPA are independent of UCP1-regulated thermogenesis or basal energy expenditure.

Past, Present and Future Anti-Obesity Effects of Flavin-Containing and/or Copper-Containing Amine Oxidase Inhibitors

“…Nevertheless, these results could be interpreted in a different light, since: 1) ephedrine is currently banned in view of its amphetamine-like structure and related adverse effects; and 2) tranylcypromine is not a simple MAOI, being now recognized as an SSAO [33] and LSD inhibitor [11,12]. Furthermore, recent studies have confirmed an anti-obesity effect for tranylcypromine even in mice invalidated for the uncoupling protein-1 (UCP1) involved in non-shivering thermogenesis and in beiging of WAT [26]. Thus, these recent findings indicate that tranylcypromine not only increases the basal metabolic rate, but it also increases spontaneous locomotor activity and decreases food intake.…”

Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice

“…The genetic inhibition of 5-HT synthesis in the brainstem decreases food intake and body weight in ob/ob mice and the wild-type mice [ 12 ]. In addition, the pharmacologic inhibition of 5-HT synthesis in the brainstem induced by treatment with a high dose PCPA (500 mg/kg) or trans-2 PCPA decreases body weight and food intake in C57BL6J mice, db/db mice [ 2 ], and high-fat diet-induced obesity [ 13 ]. Thus, the decrease in central 5-HT leads to the decrease in body weight and food intake in mice.…”

Does brainstem-derived serotonin mediate GLP-1 receptor agonist-induced suppression of appetite and body weight via 5-HT2A receptors?

“…Genetic inhibition of 5-HT synthesis in the brainstem decreases food intake and body weight in ob/ob mice and wild-type mice [2]. In addition, pharmacologic inhibition of 5-HT synthesis in the brainstem induced by treatment with a high dose of p-chlorophenylalanine (PCPA) (500 mg/kg) or trans-2 PCPA decreases body weight and food intake in C57BL6J mice, db/db mice [4], and high-fat-diet-induced obesity [5]. Thus, depletion of brainstem-derived 5-HT leads to decreases in body weight and energy intake in mice.…”