Nature子刊：中枢和外围GLP

Central and peripheral GLP-1 systems independently suppress eating

中枢和外围GLP-1系统独立抑制进食

10.1038/s42255-021-00344-4

02-15, Article

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The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut–brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut–brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

First Authors:
Daniel I Brierley

Correspondence Authors:
Guillaume de Lartigue,Stefan Trapp

All Authors:
Daniel I Brierley,Marie K Holt,Arashdeep Singh,Alan de Araujo,Molly McDougle,Macarena Vergara,Majd H Afaghani,Shin Jae Lee,Karen Scott,Calyn Maske,Wolfgang Langhans,Eric Krause,Annette de Kloet,Fiona M Gribble,Frank Reimann,Linda Rinaman,Guillaume de Lartigue,Stefan Trapp