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.
Highlights
The worldwide obesity epidemic is continuing to increase and has doubled since 1980 with an estimated 500 million obese adults and 40 million children under the age of five being overweight
Knockdown or 2-PCPA inhibition of lysine-specific demethylase 1 (LSD1) reduced adipogenesis, increased the expression of energy expenditure genes associated with mitochondrial metabolism in cultured 3T3-L1 adipocytes and in adipose tissue of high-fat-diet-fed mice, and increased oxygen consumption in 3T3-L1 adipocytes [4]
Monoamine oxidases catalyze the deamination of neurotransmitter amines and 2-PCPA inhibition of this activity has been clinically used to treat depression [2]
Summary
The worldwide obesity epidemic is continuing to increase and has doubled since 1980 with an estimated 500 million obese adults and 40 million children under the age of five being overweight. The antidepressant trans-2-phenylcyclopropylamine (2-PCPA) was associated with weight loss in rat and mouse models of diet- and genetic-induced obesity [1]. Weight loss was originally attributed to the changes in neurotransmitters as well, recent studies have found that 2-PCPA is a suicide inhibitor of the flavin adenosine dinucleotide (FAD)-dependent lysine-specificdemethylase 1, LSD1 [3]. Food intake reduction appeared to be an adaptation to 2-PCPAinduced weight loss because short-term treatment of wild type (WT) and uncoupling protein 1 (UCP1) knockout mice reduced obesity without affecting food intake. In contrast to previous reports, we conclude that orally administered 2-PCPA treatment reduces adiposity primarily by increasing spontaneous locomotor activity without significantly affecting energy expenditure or food intake
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