Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Synaptic Transmission in Energy Homeostasis Research Group, Max Planck Institute for Metabolism Research, Cologne, Germany.
Cell Rep. 2024 Jun 25;43(6):114343. doi: 10.1016/j.celrep.2024.114343. Epub 2024 Jun 11.
Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOC neuron activity via Ca imaging, we find a subpopulation of PNOC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOC) provide inhibitory input to PNOC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development.
弓状核中前强啡肽原（PNOC）表达神经元的激活可促进高脂肪饮食（HFD）诱导的过度摄食。反过来，PNOC 神经元可以抑制促黑皮质素原（POMC）神经元的厌食反应。在这里，我们验证了 PNOC 活性对于 HFD 诱导的 POMC 神经元抑制在小鼠中的必要性，并发现 PNOC 神经元依赖性的 POMC 神经元抑制是由γ-氨基丁酸（GABA）释放介导的。当通过 Ca2+成像监测单个 PNOC 神经元活性时，我们发现 PNOC 神经元的一个亚群在胃肠道感知卡路里时被抑制，而在 HFD 喂养时被去抑制。通过逆行狂犬病毒追踪和回路映射相结合，我们发现终纹床核（PNOC）的 PNOC 神经元对 PNOC 神经元提供抑制性输入，而这种抑制性输入在 HFD 喂养时减弱。这项工作揭示了饮食中卡路里含量的增加如何重塑神经元回路，为过度消费和肥胖发展铺平了道路。
