Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression

Jan 2, 2023Molecular metabolism

Obesity drug lorcaserin activates brainstem appetite-controlling neurons and boosts appetite suppression from GLP-1 receptor drugs

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Abstract

Lorcaserin significantly activated PPG neurons, which play a critical role in mediating its effects on food intake.

5-HT receptors were found to be widespread in PPG neuron clusters.
Ablating PPG neurons prevented the reduction of food intake caused by lorcaserin.
The effect of the MC4R agonist melanotan-II on food intake was not affected by PPG neuron ablation.
Combining lorcaserin with GLP-1 receptor agonists led to a greater reduction in food intake than either treatment alone.

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OBJECTIVE: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HTR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. 2C

METHODS: We profiled PPG neurons in the nucleus of the solitary tract (PPG) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGneurons for obesity medication effects on food intake by virally ablating PPGneurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. NTS NTS NTS

RESULTS: We found that 5-HTRs, but not GLP-1Rs or MC4Rs, were widespread in PPGclusters and that lorcaserin significantly activated PPGneurons. Accordingly, ablation of PPGneurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPG5-HTR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. 2C2C NTS NTS NTS NTS

CONCLUSIONS: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGneurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HTR agonists. NTS2C

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Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression

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