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

bioRxiv [Preprint]. 2023 Nov 3:2023.10.31.564990. doi: 10.1101/2023.10.31.564990.

Authors

Affiliations

¹ Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, U.S.A.
² Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology, & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, U.S.A.
³ Department of Biology, University of Virginia, Charlottesville, VA, U.S.A.
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.

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 (Trh^Arc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating Trh^Arc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing Trh^Arc 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.

Keywords: Agouti-related peptide; Energy balance; Energy homeostasis; Leptin; Melanocortin; Rabies; Saxenda; Single-cell RNA-seq; Single-cell genomics; Victoza.

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Abstract

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