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

Addison N Webster; Jordan J Becker; Chia Li; Dana C Schwalbe; Damien Kerspern; Eva O Karolczak; Elizabeth N Godschall; Dylan Matthew Belmont-Rausch; Tune H Pers; Andrew Lutas; Naomi Habib; Ali D Güler; Michael J Krashes; John N Campbell

doi:10.1101/2023.10.31.564990

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

Addison N Webster, Jordan J Becker, Chia Li, Dana C Schwalbe, Damien Kerspern, Eva O Karolczak, Elizabeth N Godschall, Dylan Matthew Belmont-Rausch, Tune H Pers, Andrew Lutas, Naomi Habib, Ali D Güler, Michael J Krashes^*, John N Campbell^*

^*Corresponding author for this work

Pers Group

Research output: Working paper › Preprint › Research

9 Downloads (Pure)

Abstract

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.

Original language	English
Publisher	bioRxiv
Number of pages	47
DOIs	https://doi.org/10.1101/2023.10.31.564990
Publication status	Published - 2023

Access to Document

10.1101/2023.10.31.564990Licence: CC BY-NC-ND

FulltextSubmitted manuscript, 9.55 MBLicence: CC BY-NC-ND

Cite this

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.

Research output: Working paper › Preprint › Research

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. / Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety. bioRxiv, 2023.

@techreport{358af600a2df418891dac08214e67319,

title = "Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety",

abstract = "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.",

author = "Webster, {Addison N} and Becker, {Jordan J} and Chia Li and Schwalbe, {Dana C} and Damien Kerspern and Karolczak, {Eva O} and Godschall, {Elizabeth N} and Belmont-Rausch, {Dylan Matthew} and Pers, {Tune H} and Andrew Lutas and Naomi Habib and G{\"u}ler, {Ali D} and Krashes, {Michael J} and Campbell, {John N}",

year = "2023",

doi = "10.1101/2023.10.31.564990",

language = "English",

publisher = "bioRxiv",

type = "WorkingPaper",

institution = "bioRxiv",

}

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 -