Delineating a Serotonin Receptor Pathway for Weight-loss Therapy

• Published in: Obesity (Silver Spring, Md.) Md.), 2022-11, Vol.30, p.27-27
• Main Authors: Li, Li, Wyler, Steven, León-Mercado, Luis, Xu, Baijie, Sohn, Jong-Woo, Liu, Chen
• Format: Article
• Language: English
• Subjects: Food; Hypothalamus
• ISSN: 1930-7381; 1930-739X

Background: The brain serotonin (5-HT) system is a critical target for multiple weight loss therapies. Notably, lorcaserin, a specific agonist for 5-HT 2C receptors (Htr2c), has been an anti-obesity medication until its recent withdrawal due to unexpected cancer risks. In search of new 5-HT based weight-loss therapies, we find that agonists for 5-HT 1B receptors (Htr1b) dose-dependently reduce food intake in mice. These include several triptans-a class of commonly prescribed anti-migraine drugs. We show that the anorectic potency of Htr1b agonists is stronger than that of lorcaserin. Furthermore, such an effect is independent of Htr2c but requires endogenous Htr1b. Methods: By ablating Htr1b in four different brain regions, we demonstrate that Htr1b engages in spatiotemporally segregated neural pathways to regulate postnatal growth and the anorectic response to 5-HT agents. Moreover, these studies reveal AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) as one critical site that mediates the hypophagic effects of Htr1b agonists. Results: To further probe the neural basis of the anorexigenic Htr1b circuit, we have generated and characterized Htr1b-Cre mice. We find that ARH Htr1b neurons activate in response to food deprivation. Moreover, chemogenetic activation of these neurons promotes food intake whereas their inhibition suppresses hunger. Single-nucleus RNA sequencing analyses reveal that Htr1b marks a subset of AgRP neurons lacking leptin receptor expression. We next use an intersectional genetic approach to specifically target the subset of AgRP neurons expressing Htr1b (Htr1bAgRP neurons). We find that the cell bodies of these neurons are uniquely positioned at the mediobasal part of the ARH. Furthermore, Htr1bAgRP neurons preferentially innervate the paraventricular nucleus of the hypothalamus (PVH). Consistent with these findings, we show that Htr1bAgRP neurons directly regulate food intake through a Htr1bAgRP → PVH circuit. Conclusions: A loss of appetite has been noted in patients taking triptans. By illustrating a 5-HT receptor pathway for appetite suppression, our findings highlight the therapeutic potential for Htr1b agonists as a novel weight loss therapy.