Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss

Authors: HE, YANG - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIANG, CHEN - Children'S Nutrition Research Center (CNRC); WANG, JULIA - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); WANG, LINA - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Pennington Biomedical Research Center; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC); WU, QI - Children'S Nutrition Research Center (CNRC); SUN, ZHENG - Baylor College Of Medicine; TONG, QINGCHUN - University Of Texas Health Science Center; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/27/2021
Publication Date: 6/30/2021
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. Journal of Neuroscience. 41(26):5734-5746. https://doi.org/10.1523/JNEUROSCI.3210-20.2021.
DOI: https://doi.org/10.1523/JNEUROSCI.3210-20.2021

Interpretive Summary: Obesity, resulting from overeating and energy imbalance, is a serious health issue to our society and treatment for the disease is limited. Here we showed that a novel small chemical, namely barbadin, can potentiate and prolong the weight-lowering effect of a former FDA-approved anti-obesity drug, lorcaserin. This work provides a framework to facilitate development of more effective weight management regimen. Our findings are of importance as a means to understand causes of obesity and nutritional and other strategies to prevent this chronic disease.

Technical Abstract: Obesity is a serious global health problem due to its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G protein-coupled receptor, activates pro-opiomelanocortin (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, suffer from diminished efficacy to reduce weight after prolonged administration. Here we show that barbadin, a novel B-arrestin/B2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of lorcaserin to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that barbadin co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged lorcaserin exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation 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 lorcaserin or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.