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

Webster, A. N.; Becker, J. J.; Li, C.; Schwalbe, D. C.; Kerspern, D.; Karolczak, E. O.; Godschall, E. N.; Belmont-Rausch, D. M.; Pers, T. H.; Lutas, A.; Habib, N.; Guler, A. D.; Krashes, M. J.; Campbell, J. N.

doi:10.1101/2023.10.31.564990

bioRxiv · 10.1101/2023.10.31.564990

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

Webster, A. N.·Becker, J. J.·Li, C.·Schwalbe, D. C.·Kerspern, D.·Karolczak, E. O.·Godschall, E. N.·Belmont-Rausch, D. M.·Pers, T. H.·Lutas, A.·Habib, N.·Guler, A. D.·Krashes, M. J.·Campbell, J. N.

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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. One potential mechanism is by activating neurons which inhibit 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-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides 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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Webster, A. N., Becker, J. J., Li, C., Schwalbe, D. C., Kerspern, D., Karolczak, E. O., Godschall, E. N., Belmont-Rausch, D. M., Pers, T. H., Lutas, A., Habib, N., Guler, A. D., Krashes, M. J., Campbell, J. N.. 2023-11-03. Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety. https://doi.org/10.1101/2023.10.31.564990

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