Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety
Publikation: Working paper › Preprint › Forskning
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Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety. / Webster, Addison N; Becker, Jordan J; Li, Chia; Schwalbe, Dana C; Kerspern, Damien; Karolczak, Eva O; Godschall, Elizabeth N; Belmont-Rausch, Dylan Matthew; Pers, Tune H; Lutas, Andrew; Habib, Naomi; Güler, Ali D; Krashes, Michael J; Campbell, John N.
bioRxiv, 2023.Publikation: Working paper › Preprint › Forskning
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TY - UNPB
T1 - Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety
AU - Webster, Addison N
AU - Becker, Jordan J
AU - Li, Chia
AU - Schwalbe, Dana C
AU - Kerspern, Damien
AU - Karolczak, Eva O
AU - Godschall, Elizabeth N
AU - Belmont-Rausch, Dylan Matthew
AU - Pers, Tune H
AU - Lutas, Andrew
AU - Habib, Naomi
AU - Güler, Ali D
AU - Krashes, Michael J
AU - Campbell, John N
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1101/2023.10.31.564990
DO - 10.1101/2023.10.31.564990
M3 - Preprint
C2 - 37961449
BT - Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety
PB - bioRxiv
ER -
ID: 379586424