Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Publikation: Working paperPreprintForskning


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  • Addison N Webster
  • Jordan J Becker
  • Chia Li
  • Dana C Schwalbe
  • Damien Kerspern
  • Eva O Karolczak
  • Elizabeth N Godschall
  • Belmont-Rausch, Dylan Matthew
  • Pers, Tune H
  • Andrew Lutas
  • Naomi Habib
  • Ali D Güler
  • Michael J Krashes
  • John N Campbell
Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide’s satiating effects. Our
results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.
Antal sider47
StatusUdgivet - 2023

ID: 379586424