| First Author | He Y | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 26 | Pages | 5734-5746 |
| PubMed ID | 34031163 | Mgi Jnum | J:336036 |
| Mgi Id | MGI:7485907 | Doi | 10.1523/JNEUROSCI.3210-20.2021 |
| Citation | He Y, et al. (2021) Barbadin Potentiates Long-Term Effects of Lorcaserin on POMC Neurons and Weight Loss. J Neurosci 41(26):5734-5746 |
| abstractText | Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT(2C)R), 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 beta-arrestin/beta2-adaptin inhibitor, can prevent 5-HT(2C)R 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-HT(2C)R in POMC(ARH) 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-HT(2C)R desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT(2C)R agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT(2C)R desensitization.SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT(2C)R) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT(2C)R agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines. |
