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. 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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