Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss
Document Type
Article
Publication Date
6-30-2021
Abstract
Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel b-arrestin/b2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.
Recommended Citation
He, Y., Liu, H., Yin, N., Yang, Y., Wang, C., Yu, M., Liu, H., Liang, C., Wang, J., Tu, L., Zhang, N., Wang, L., He, Y., Fukuda, M., Wu, Q., Sun, Z., Tong, Q., & Xu, Y. (2021). Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss. Retrieved from https://repository.lsu.edu/pbrc_basic_science_pubs/45