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

Autor: Webster AN; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA., Becker JJ; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Li C; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Schwalbe DC; Department of Biology, University of Virginia, Charlottesville, VA, USA., Kerspern D; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Karolczak EO; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Bundon CB; Department of Biology, University of Virginia, Charlottesville, VA, USA., Onoharigho RA; Department of Biology, University of Virginia, Charlottesville, VA, USA., Crook M; Department of Biology, University of Virginia, Charlottesville, VA, USA., Jalil M; Department of Biology, University of Virginia, Charlottesville, VA, USA., Godschall EN; Department of Biology, University of Virginia, Charlottesville, VA, USA., Dame EG; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Dawer A; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Belmont-Rausch DM; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Pers TH; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Lutas A; Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA., Habib N; Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel., Güler AD; Department of Biology, University of Virginia, Charlottesville, VA, USA., Krashes MJ; 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., Campbell JN; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. jnc4e@virginia.edu.; Department of Biology, University of Virginia, Charlottesville, VA, USA. jnc4e@virginia.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Dec; Vol. 6 (12), pp. 2354-2373. Date of Electronic Publication: 2024 Dec 03.
DOI: 10.1038/s42255-024-01168-8
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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