陆军军医大学学报2026，Vol.48Issue(6)：687-700,14.DOI:10.16016/j.2097-0927.202512099
测序解析3种肥胖模型小鼠下丘脑神经通讯特征:抑制性调控减弱,谷氨酸、NO与电突触信号各显主导
Hypothalamic neural communication characteristics in 3 mouse models based on sequencing analysis:Attenuated inhibitory regulation with dominant roles of glutamate,NO,and electrical synapse signaling
摘要
Abstract
Objective To compare the hypothalamic cellular composition and neuron-neuron communication networks across 3 etiologically distinct mouse models of obesity,high-fat diet(HFD),leptin-deficient(ob/ob),and leptin receptor-deficient(db/db)so as to identify universal mechanistic clues that can be validated across etiologies and searching for etiology-specific targets applicable to stratified treatment.Methods Six-week-old male C57 mice were fed with HFD continuously until 18 weeks of age to establish a HFD model.In parallel,18-week-old male ob/ob mice and db/db mice were subjected as genetic obesity models,and age-matched male C57 mice served as controls.Three mice were included per group(n=3),totaling 12 mice,were euthanized,and the hypothalamic tissues were meticulously dissected under a stereomicroscope.Single-nucleus transcriptome sequencing(snRNA-seq)was performed using the 10x Genomics v3.1 platform.The obtained sequencing data were aligned with Cell Ranger and processed in Seurat for quality control,dimensionality reduction,and clustering.Subsequently,neuron-neuron communication networks were inferred based on NeuronChat and its nervous system-specific ligand-receptor database,systematically comparing changes in differential communication networks,signal output/input strength,information flow,and interaction quantity between each obesity model and C57 controls.Results Dimensionality reduction and clustering of hypothalamic snRNA-seq data from C57,HFD,ob/ob,and db/db mice identified several major cell populations,including excitatory neurons,inhibitory neurons,and multiple non-neuronal cell types,with cells of the same type showing model-dependent shifts in uniform manifold approximation and projection(UMAP)space.Neuronal subclustering resolved 7 GABAergic and 10 glutamatergic subtypes,indicating pronounced neuronal heterogeneity in the hypothalamus.Across the 3 obese models,GABAergic inhibitory incoming signaling and the neurexin-neuroligin(Nrxn-Nlgn)pathway were broadly downregulated.Meanwhile,each model exhibited a distinct communication-network signature:the HFD model was characterized by enhanced electrical synapses mediated by gap junction protein alpha-1(Gja1-Gja1)and reduced Nrxn-Nlgn output;the db/db model showed dominant nitric oxide-soluble guanylate cyclase signaling(NO-Gucy1a2)together with enrichment of prodynorphin(Pdyn)-related pathways;the ob/ob model was primarily marked by enhanced glutamate receptor interactions.Pairwise comparisons among models further validated these patterns:HFD relatively enriched Gja1-related signaling and certain metabotropic glutamate receptor interactions;db/db relatively enriched NO-Gucy1a2 and synaptic adhesion-related pathways;ob/ob relatively enriched in ionotropic/metabotropic glutamate receptor interactions.Conclusion Distinct neural communication network patterns exist in the hypothalamus across obesity models of different etiologies:diet-induced obesity preferentially exhibits enhanced electrical synapse-related pathways,leptin receptor-deficient model is primarily characterized by increased NO-related signaling,and the leptin-deficient model is centrally distinguished by enhanced glutamatergic excitatory interactions.Notably,attenuated inhibitory regulation emerges as a common feature across models,providing novel insights into understanding the pathological mechanisms underlying obesity development.关键词
肥胖模型/下丘脑/单细胞核测序/神经通讯/配体-受体互作Key words
obesity animal models/hypothalamus/single-nucleus RNA sequencing/neuronal communication/ligand-receptor interactions分类
医药卫生引用本文复制引用
周连宇,费兴杭,尹华春,臧振乐,郑新,范晓棠,李松,杨辉..测序解析3种肥胖模型小鼠下丘脑神经通讯特征:抑制性调控减弱,谷氨酸、NO与电突触信号各显主导[J].陆军军医大学学报,2026,48(6):687-700,14.基金项目
国家自然科学基金(32471027),重庆市科技创新与应用发展专项(CSTB2024TIAD-STX0044)和重庆市自然科学基金(CSTB2024NSCQ-MSX0021) Supported by the National Natural Science Foundation of China(32471027),the Special Project of Science and Technology Innovation and Application Development of Chongqing(CSTB2024TIAD-STX0044),and the Natural Science Foundation of Chongqing(CSTB2024NSCQ-MSX0021). （32471027）
