Furthermore, nuclear magnetic resonance analyses revealed that frovatriptan infusion reduced fat mass, but not lean mass, after the 14-d treatment ( Fig. In another paradigm, chronic (14-d) infusion of frovatriptan (7 mg/kg/d) via implanted osmotic minipumps yielded a similar weight loss (−2.3 ± 1.75% vs.
Consistent with this finding, frovatriptan-treated mice had decreased food intake compared to vehicle-treated controls ( Fig. In contrast, vehicle-treated controls gained 5.83 ± 2.04% weight during the same period. A daily IP dose of frovatriptan (10 mg/kg) reduced body weight in HFD-fed mice by 3.58 ± 1.61% within 24 d ( Fig. Obese mice (>40 g) with comparable weights were then segregated into two groups and treated with either frovatriptan or vehicle while still being fed HFD. Briefly, male C57BL/6J mice were fed a high-fat diet (HFD, 60 kcal% fat, D12492i Research Diets) for 7 wk. We next evaluated the anti-obesity effect of frovatriptan in diet-induced obese mice ( Fig. Collectively, our findings suggest that Htr1b is a new target for 5-HT–based weight-loss therapies. Using a combination of genetic, transcriptomic, and behavioral analyses, we have investigated the underlying neural pathways behind the pharmacological and physiological effects of Htr1b activation on food intake and body weight. Furthermore, such an effect was independent of Htr2c but required endogenous Htr1b. Notably, the anorectic effect of Htr1b-specific agonists appeared to be more potent than that of lorcaserin, the specific agonist for Htr2c. These include several triptans, a class of commonly used antimigraine drugs that manifest few health risks after long-term use ( Ghanshani et al., 2020 Robbins, 2004). In search of new 5-HT–based weight-loss therapies, we found that agonists for 5-HT 1B receptor ( Htr1b) dose-dependently reduced food intake in C57BL/6 mice. These findings, therefore, suggest the involvement of additional 5-HT receptors behind the hypophagic effect. Observations in humans and mice showed that the anorectic effect of lorcaserin is less potent than that of d-fenfluramine or other serotonergic agents ( Berglund et al., 2013 Colman et al., 2012).
Unfortunately, lorcaserin was recently removed from the market due to unexpected cancer risk ( Sharretts et al., 2020), casting doubt on the future use of other Htr2c agonists as anti-obesity therapies.
Subsequently, lorcaserin (Belviq), an Htr2c-specific agonist, became the first novel anti-obesity medication in 1997 ( Colman et al., 2012). The therapeutic potential of this pathway was highlighted by the observation that the anorectic effect of d-fenfluramine, the active ingredient of the once-popular diet pill fenfluramine/phentermine, was mediated, in part, through the activation of 5-HT 2C receptors ( Htr2c Heisler et al., 2002 Tecott et al., 1995). Compounds that elevate brain 5-HT content reduce food intake and body weight ( Wyler et al., 2017). In this regard, the central serotonin (5-HT) system has been a target for multiple weight-loss medications since the 1960s. However, despite these advances, druggable targets with well-illustrated mechanisms for appetite control remain scarce.
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With the help of new optogenetic, chemogenetic, and neuroimaging tools, recent studies have uncovered a series of neural circuits that control food intake ( Moran and Ladenheim, 2016). In support of this notion, many obesity-linked genes are present in the brain and have been shown to regulate satiety ( O’Rahilly, 2009). Excessive caloric intake is the primary cause of weight gain. Obesity significantly increases the mortality risk for many diseases, including COVID-19 ( Poly et al., 2021). We show that they regulate food intake, in part, through a Htr1b AgRP→PVH circuit. Finally, we used an intersectional approach to specifically target these neurons (Htr1b AgRP neurons). Furthermore, single-nucleus RNA sequencing analyses revealed that Htr1b marks a subset of AgRP neurons. We find that ARH Htr1b neurons bidirectionally regulate food intake in vivo. To further study the anorexigenic Htr1b circuit, we generated Htr1b-Cre mice. Moreover, Htr1b in AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) contributes to the hypophagic effects of HTR1B agonists. By ablating Htr1b in four different brain regions, we demonstrate that Htr1b engages in spatiotemporally segregated neural pathways to regulate postnatal growth and food intake. Moreover, the anorectic effect depends on the serotonin (5-HT) 1B receptor ( Htr1b). In particular, frovatriptan treatment reduces food intake and body weight in diet-induced obese mice. Here, we report a previously unrecognized role for them to suppress appetite in mice. Triptans are a class of commonly prescribed antimigraine drugs.
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