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

Nat Metab. 2024 Dec 3. doi: 10.1038/s42255-024-01168-8. Online ahead of print.

Authors

Addison N Webster^#¹, Jordan J Becker^#², Chia Li², Dana C Schwalbe³, Damien Kerspern², Eva O Karolczak², Catherine B Bundon³, Roberta A Onoharigho³, Maisie Crook³, Maira Jalil³, Elizabeth N Godschall³, Emily G Dame², Adam Dawer², Dylan Matthew Belmont-Rausch⁴, Tune H Pers⁴, Andrew Lutas², Naomi Habib⁵, Ali D Güler³, Michael J Krashes⁶, John N Campbell^{7

8}

Affiliations

¹ Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA.
² Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
³ Department of Biology, University of Virginia, Charlottesville, VA, USA.
⁴ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
⁵ Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
⁶ Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA. michael.krashes@nih.gov.
⁷ Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. jnc4e@virginia.edu.
⁸ Department of Biology, University of Virginia, Charlottesville, VA, USA. jnc4e@virginia.edu.

^# Contributed equally.

PMID: 39627618
DOI: 10.1038/s42255-024-01168-8

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.

Abstract

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