Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
Cell Metab. 2023 Jun 6;35(6):979-995.e7. doi: 10.1016/j.cmet.2023.04.020. Epub 2023 May 17.
Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons.
弓状核（ARC）中的神经肽 Y（NPY）被认为是进食的最重要调节因子之一。然而，在肥胖状态下 NPY 如何促进进食仍不清楚。在这里，我们发现高脂肪饮食（HFD）或遗传性肥胖瘦素受体缺陷小鼠引起的正能量平衡会导致 Npy2r 表达升高，尤其是在促黑皮质素原（POMC）神经元上，这也改变了瘦素的反应性。回路映射确定了一小部分 ARC 刺鼠相关肽（Agrp）阴性 NPY 神经元，它们控制这些表达 Npy2r 的 POMC 神经元。该新发现的回路的化学遗传激活强烈驱动进食，而光遗传抑制则减少进食。与之一致的是，POMC 神经元上缺乏 Npy2r 会导致食物摄入量和脂肪量减少。这表明在能量过剩的情况下，当 ARC NPY 水平普遍下降时，POMC 神经元上高亲和力的 NPY2R 仍然能够通过主要由 Agrp 阴性 NPY 神经元释放的 NPY 驱动进食并增强肥胖的发展。
