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; Catherine B. Bundon; Roberta A. Onoharigho; Maisie Crook; Maira Jalil; Elizabeth N. Godschall; Emily G. Dame; Adam Dawer; Dylan Matthew Belmont-Rausch; Tune H. Pers; Andrew Lutas; Naomi Habib; Ali D. Güler; Michael J. Krashes; John N. Campbell

doi:10.1038/s42255-024-01168-8

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, Catherine B. Bundon, Roberta A. Onoharigho, Maisie Crook, Maira Jalil, Elizabeth N. Godschall, Emily G. Dame, Adam Dawer, 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

Edmond & Lily Safra Center for Brain Sciences

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)⁺ Arc (TRH^Arc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRH^Arc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRH^Arc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

Original language	English
Pages (from-to)	2354-2373
Number of pages	20
Journal	Nature Metabolism
Volume	6
Issue number	12
DOIs	https://doi.org/10.1038/s42255-024-01168-8
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s42255-024-01168-8

Cite this

Webster, A. N., Becker, J. J., Li, C., Schwalbe, D. C., Kerspern, D., Karolczak, E. O., Bundon, C. B., Onoharigho, R. A., Crook, M., Jalil, M., Godschall, E. N., Dame, E. G., Dawer, A., Belmont-Rausch, D. M., Pers, T. H., Lutas, A., Habib, N., Güler, A. D., Krashes, M. J., & Campbell, J. N. (2024). Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety. Nature Metabolism, 6(12), 2354-2373. https://doi.org/10.1038/s42255-024-01168-8

@article{2f36e763028040d18688eb4cde910e4e,

title = "Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety",

abstract = "Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide{\textquoteright}s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit 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 Bundon, {Catherine B.} and Onoharigho, {Roberta A.} and Maisie Crook and Maira Jalil and Godschall, {Elizabeth N.} and Dame, {Emily G.} and Adam Dawer 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.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

year = "2024",

month = dec,

doi = "10.1038/s42255-024-01168-8",

language = "אנגלית",

volume = "6",

pages = "2354--2373",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer Berlin",

number = "12",

}

Webster, AN, Becker, JJ, Li, C, Schwalbe, DC, Kerspern, D, Karolczak, EO, Bundon, CB, Onoharigho, RA, Crook, M, Jalil, M, Godschall, EN, Dame, EG, Dawer, A, Belmont-Rausch, DM, Pers, TH, Lutas, A, Habib, N, Güler, AD, Krashes, MJ & Campbell, JN 2024, 'Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety', Nature Metabolism, vol. 6, no. 12, pp. 2354-2373. https://doi.org/10.1038/s42255-024-01168-8

TY - JOUR

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 - Bundon, Catherine B.

AU - Onoharigho, Roberta A.

AU - Crook, Maisie

AU - Jalil, Maira

AU - Godschall, Elizabeth N.

AU - Dame, Emily G.

AU - Dawer, Adam

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 - 2024/12

Y1 - 2024/12

N2 - Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

AB - Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

UR - http://www.scopus.com/inward/record.url?scp=85211506316&partnerID=8YFLogxK

U2 - 10.1038/s42255-024-01168-8

DO - 10.1038/s42255-024-01168-8

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 39627618

AN - SCOPUS:85211506316

SN - 2522-5812

VL - 6

SP - 2354

EP - 2373

JO - Nature Metabolism

JF - Nature Metabolism

IS - 12

ER -

Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this