Lorcaserin is a serotonin 5HT-2c receptor agonist effective in treating obesity. While studies in rodents have shown that lorcaserin acts in the brain to exert its weight reducing effects, this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants to study the effects of lorcaserin on the brain using functional magnetic resonance imaging (fMRI). Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in amygdala, parietal and visual cortices at baseline. These data suggest that lorcaserin exerts its weight reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices), as well as emotional/limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.
Previous use of serotonergic agonists, such as fenfluramine, are linked to non-selective activation of 5-HT2 receptors that led to various cardiac problems (2). However, since a 5-HT2c receptor antagonist blocked the weight reducing effects of fenfluramine, the more selective activation of 5-HT2c receptors by lorcaserin would produce this anti-obesity benefit seemingly without cardiac risk (3). Knock-out mice for the 5-HT2c receptors show higher body weight as a result of abnormal food consumption, further confirming the role of this receptor in obesity (4). These animals exhibit changes in metabolic hormones, developing insulin and leptin resistance and moreover impaired glucose tolerance, in addition to prolonged meal duration and frequency (4; 5). A similar mechanism may contribute to the significant improvement in the levels of fasting serum glucose, total cholesterol, triglycerides and blood pressure seen in patients treated with lorcaserin (6-8).
- Received May 18, 2016.
- Accepted June 29, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.