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

30 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

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

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10.1038/s42255-024-01168-8

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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",

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journal = "Nature Metabolism",

issn = "2522-5812",

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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

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AU - Webster, Addison N.

AU - Becker, Jordan J.

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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

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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.

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ER -

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

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