140-OR: Inhibition of Serotonin 2c Receptor Internalization Potentiates Lorcaserin Effect on Body Weight Loss.

As a body weight management medicine, lorcaserin, a selective agonist of serotonin 2C receptor (5-HT_2CR) which is a G protein-coupled receptor, fails to maintain its effect on body weight loss after a long term administration. Thus, it is necessary to find a way to strengthen its effect on obesity treatment. It has been reported that the effect of lorcaserin on body weight loss is by activating Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARH). However, how POMC^ARH neuron activity changes after long term lorcaserin treatment remains unknown. In the present study, we found that POMC^ARH neurons cannot maintain its sensitivity to further lorcaserin stimulation after a long term lorcaserin treatment. By using in vitro electrophysiology recording and c-Fos immunostaining in the brain slice from control mice, we found that acute lorcaserin application significantly increased POMC^ARH neuron activity. However, this activation effect significantly decreased in mice with lorcaserin administration for consecutive 20 days. By in vivo fiber photometry calcium recording, we found that lorcaserin significantly increased POMC^ARH neuron activity in vivo at first day, but this activation effect decreased after 10 days lorcaserin treatment and almost disappeared after 20 days lorcaserin treatment. We further showed that this desensitization of POMC^ARH neurons to lorcaserin stimulation is mainly due to a beta-arrestin-mediated excessive internalization of 5-HT_2C receptor in POMC^ARH neurons. Barbadin, a novel selective β-arrestin/adaptor protein 2 interaction inhibitor, maintains POMC^ARH neuron sensitivity to further lorcaserin stimulation by blocking prolonged lorcaserin-induced aberrant 5-HT_2C receptor internalization. Co-treatment with barbadin also prolongs lorcaserin's effect on body weight loss and food intake reduction in mice. Overall, our results may provide a potential strategy for facilitating obesity treatment by lorcaserin. Disclosure: Y. He: None. H. Liu: None. Y. Xu: None. [ABSTRACT FROM AUTHOR]