title: Visceral White Adipose Tissue after Chronic Intermittent and Sustained Hypoxia in Mice.
abstract: Angiogenesis, a process induced by hypoxia in visceral white adipose tissues (vWAT) in the context of obesity, mediates obesity-induced metabolic dysfunction and insulin resistance. Chronic intermittent hypoxia (IH) and sustained hypoxia (SH) induce body weight reductions and insulin resistance of different magnitudes, suggesting different hypoxia inducible factor (HIF)-1α-related activity. Eight-week-old male C57BL/6J mice (n = 10-12/group) were exposed to either IH, SH, or room air (RA). vWAT were analyzed for insulin sensitivity (phosphorylated (pAKT)/AKT), HIF-1α transcription using chromatin immunoprecipitation (ChIP)-sequencing, angiogenesis using immunohistochemistry, and gene expression of different fat cell markers and HIF-1α gene targets using quantitative polymerase chain reaction or microarrays. Body and vWAT weights were reduced in hypoxia (SH > IH > RA; P < 0.001), with vWAT in IH manifesting vascular rarefaction and increased proinflammatory macrophages. HIF-1α ChIP-sequencing showed markedly increased binding sites in SH-exposed vWAT both at 6 hours and at 6 weeks compared with IH, the latter also showing decreased vascular endothelial growth factor, endothelial nitric oxide synthase, P2RX5, and PAT2 expression, and insulin resistance (IH > > > SH = RA; P < 0.001). IH induces preferential whitening of vWAT, as opposed to prominent browning in SH. Unlike SH, IH elicits early HIF-1α activity that is unsustained over time and is accompanied by concurrent vascular rarefaction, inflammation, and insulin resistance. Thus, the dichotomous changes in HIF-1α transcriptional activity and brown/beige/white fat balance in IH and SH should enable exploration of mechanisms by which altered sympathetic outflow, such as that which occurs in apneic patients, results in whitening, rather than the anticipated browning of adipose tissues that occurs in SH.
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: David
authors.identifier: 0000-0001-8195-6036
authors.initials: D
authors.lastname: Gozal
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: Alex
authors.initials: A
authors.lastname: Gileles-Hillel
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: Rene
authors.initials: R
authors.lastname: Cortese
authors.affiliation: 2 Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, Illinois.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.|3 Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona-IDIBAPS, Barcelona, Spain; and.|4 CIBER de Enfermedades Respiratorias, Barcelona, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Almendros
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: Zhuanhong
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: Ahamed A
authors.initials: AA
authors.lastname: Khalyfa
authors.affiliation: 2 Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, Illinois.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: 1 Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, and.
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052436:Adipose Tissue, White / Q000473:pathology*; D000818:Animals; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism; D002908:Chronic Disease; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D050152:Intra-Abdominal Fat / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D000263:Adenylate Kinase; D000071193:Autophagy-Related Protein 7; D010100:Oxygen
keywords: adipose tissue; angiogensis; hypoxia-inducible factor; inflammation; insulin resistance