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<p>Central glucagon-like peptide-1 (GLP-1), secreted by a distinct population of nucleus tractus solitarius neurons, suppresses feeding but the exact mechanisms of action in the brain remain unclear. Here, we investigate a descending circuit formed by GLP-1 receptor (GLP-1R) neurons in the paraventricular hypothalamic nucleus (PVN<sup>GLP-1R</sup>) projecting to the dorsal vagal complex (DVC) of the brain stem in mice. PVN<sup>GLP-1R</sup>→DVC synapses release glutamate and are augmented by GLP-1. Chemogenetic activation of PVN<sup>GLP-1R</sup>→DVC suppresses feeding. Under an energy deficit (that is, hunger) state, synaptic strength is weaker but is more profoundly augmented by GLP-1R activation than under energy-replete state. In an obese condition, the dynamic synaptic changes in this circuit are disrupted. Optogenetic activation of PVN<sup>GLP-1R</sup>→DVC projections suppresses food intake energy state dependently, and blocking its synaptic release or ablating GLP-1Rs in the presynaptic neurons impairs metabolic health. These findings indicate that the state-dependent synaptic regulation by GLP-1 in PVN<sup>GLP-1R</sup>→DVC descending circuit is important for energy homeostasis.</p>

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State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis

  • 期刊论文

  • 发表日期：

    2025年6月4日

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  • Le Wang,
  • Rohan H. Savani,
  • Yi Lu,
  • Matteo Bernabucci,
  • Jorge Luis-Islas,
  • Erin Park,
  • Ishnoor Singh,
  • Wei Xu,
  • Abdelfattah El Ouaamari,
  • Michael B. Wheeler,
  • Harvey J. Grill,
  • Mark A. Rossi,
  • Zhiping P. Pang

摘要

Central glucagon-like peptide-1 (GLP-1), secreted by a distinct population of nucleus tractus solitarius neurons, suppresses feeding but the exact mechanisms of action in the brain remain unclear. Here, we investigate a descending circuit formed by GLP-1 receptor (GLP-1R) neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) projecting to the dorsal vagal complex (DVC) of the brain stem in mice. PVNGLP-1R→DVC synapses release glutamate and are augmented by GLP-1. Chemogenetic activation of PVNGLP-1R→DVC suppresses feeding. Under an energy deficit (that is, hunger) state, synaptic strength is weaker but is more profoundly augmented by GLP-1R activation than under energy-replete state. In an obese condition, the dynamic synaptic changes in this circuit are disrupted. Optogenetic activation of PVNGLP-1R→DVC projections suppresses food intake energy state dependently, and blocking its synaptic release or ablating GLP-1Rs in the presynaptic neurons impairs metabolic health. These findings indicate that the state-dependent synaptic regulation by GLP-1 in PVNGLP-1R→DVC descending circuit is important for energy homeostasis.