{"database":"biostudies-arrayexpress","file_versions":[],"scores":null,"additional":{"submitter":["Annie Yew"],"organism":["Mus musculus"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/E-MTAB-16066"],"description":["Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional visualization, we show that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals robust upregulation of neurotrophic and browning-associated genes, including neuregulin 4 (NRG4), which we identify as a key mediator of sympathetic neurite growth. Co-culture experiments with SH-SY5Y neuron-like cells and WAT explants suggest that IF-treated WAT promotes neurite branching via the NRG4-ErbB4 pathway. Inhibition of NRG4-ErbB4 pathway abrogates this effect, confirming its role in IF-induced sympathetic remodeling. Moreover, analysis of human visceral adipose tissue RNA-seq data shows a strong positive correlation between NRG4 expression and browning gene signatures. Together, these findings uncover a previously unappreciated role of IF in driving sympathetic remodeling of WAT via NRG4, offering mechanistic insights into its metabolic benefits and revealing a potential therapeutic target for obesity-related disorders."],"repository":["biostudies-arrayexpress"],"sample_protocol":["Nucleic Acid Extraction - Adipose samples were lysed using TRIzol reagent. Total RNA was extracted using the Direct-zol RNA MiniPrep kit (Zymo Research)","Library Construction - cDNA libraries were generated using the Nugen Ovation SPIA chemistry with a fully automated Wafergen’s Apollo liquid handler","Sequencing - Sequencing was performed on an Illumina HiSeq 2000 platform using single-end 1×50 bp reads following the standard Illumina protocol.","Sample Collection - Perigonadal white adipose tissue was dissected from mice after cervical dislocation while under isoflurane euthanasia. Tissue was immediately frozen in liquid nitrogen after dissection"],"figure_sub":["Organization","MINSEQE Score","Assays and Data","Processed Data","MAGE-TAB Files"],"data_protocol":["Data Transformation - The reads were aligned to the GRCm38 mouse genome (Ensembl release 80) by STAR (v2.4.2a). Read alignments were merged and disambiguated, and a single BAM (Binary Alignment Mapped) file output per library or sample was used. BAM files were then additionally filtered to remove reads with a mapping quality (MAPQ) less than 13, and all ribosomal and mitochondrial RNA reads. Alignments were assembled using Cufflinks (v2.2.1) using the –g parameter to construct a genome annotation file against the reference gene model (Ensembl release 80) and to identify novel transcripts. Raw read counts were obtained by mapping reads at the gene level using the Cufflinks assembled transcript annotation file with HTSeq-count tool from the Python package HTSeq, at http://www.huber.embl.de/users/anders/HTSeq/doc/count.html, using intersection- nonempty counting mode."],"omics_type":["Metabolomics","Unknown","Transcriptomics","Genomics","Proteomics"],"instrument_platform":["Isoflurane euthanasia chamber","Nugen Ovation SPIA; Wafergen’s Apollo liquid handler; KAPA Hyper Prep Library Kit","QIAGEN TissueLyser II","Illumina HiSeq 2000","Python"],"pubmed_abstract":["Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders."],"study_type":["RNA-seq of total RNA"],"species":["Mus musculus"],"pubmed_title":["Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage"],"pubmed_authors":["Annie Yew","Yining Zhang","Nathaniel Vo","Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung","Jin G. Park","Hoon-Ki Sung"],"additional_accession":[]},"is_claimable":false,"name":"Intermittent fasting promotes remodeling of neural and vascular networks in visceral white adipose tissue","description":"Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional visualization, we show that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals robust upregulation of neurotrophic and browning-associated genes, including neuregulin 4 (NRG4), which we identify as a key mediator of sympathetic neurite growth. Co-culture experiments with SH-SY5Y neuron-like cells and WAT explants suggest that IF-treated WAT promotes neurite branching via the NRG4-ErbB4 pathway. Inhibition of NRG4-ErbB4 pathway abrogates this effect, confirming its role in IF-induced sympathetic remodeling. Moreover, analysis of human visceral adipose tissue RNA-seq data shows a strong positive correlation between NRG4 expression and browning gene signatures. Together, these findings uncover a previously unappreciated role of IF in driving sympathetic remodeling of WAT via NRG4, offering mechanistic insights into its metabolic benefits and revealing a potential therapeutic target for obesity-related disorders.","dates":{"release":"2026-07-13T00:00:00Z","modification":"2026-07-13T17:43:59.434Z","creation":"2025-11-06T12:58:37.824Z"},"accession":"E-MTAB-16066","cross_references":{"pubmed":["29039412"],"ENA":["ERP183698"],"EFO":["EFO_0002944","EFO_0004170","EFO_0009653","EFO_0005518","EFO_0003816","EFO_0004184"],"doi":["10.1038/cr.2017.126"]}}