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  • American Physiological Society  (5)
  • 1
    Online Resource
    Online Resource
    Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity
    American Physiological Society ; 2022
    In:  Physiological Genomics Vol. 54, No. 6 ( 2022-06-01), p. 206-219
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 54, No. 6 ( 2022-06-01), p. 206-219
    Abstract: Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene coexpression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the “African American Genetics of Metabolism and Expression” and “Metabolic Syndrome in Men.” We used weighted gene coexpression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous “consensus genes” whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight coexpressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization, and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b), or no previously known role in obesity (e.g., St14 and Ms4a6a). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00172.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 2031330-5
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  • 2
    Online Resource
    Online Resource
    Skeletal muscle extracellular matrix remodeling with worsening glycemic control in nonhuman primates
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 320, No. 3 ( 2021-03-01), p. R226-R235
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 320, No. 3 ( 2021-03-01), p. R226-R235
    Abstract: Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for 〉 80% of circulating glucose uptake. The goals of this study were to assess changes in global- and location-level gene expression, remodeling proteins, fibrosis, and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting, and immunostaining. We evaluated SkM samples from health-diverse African green monkeys ( Cholorcebus aethiops sabaeus) to investigate these relationships. We assessed SkM remodeling at the molecular level by evaluating unbiased transcriptomics in age-, sex-, weight-, and waist circumference-matched metabolically healthy, prediabetic (PreT2D) and T2D monkeys ( n = 13). Our analysis applied novel location-specific gene differences and shows that extracellular facing and cell membrane-associated genes and proteins are highly upregulated in metabolic disease. We verified transcript patterns using immunohistochemical staining and protein analyses of matrix metalloproteinase 16 (MMP16), tissue inhibitor of metalloproteinase 2 (TIMP2), and VEGF. Extracellular matrix (ECM) functions to support intercellular communications, including the coupling of capillaries to muscle cells, which was worsened with increasing blood glucose. Multiple regression modeling from age- and health-diverse monkeys ( n = 33) revealed that capillary density was negatively predicted by only fasting blood glucose. The loss of vascularity in SkM co-occurred with reduced expression of hypoxia-sensing genes, which is indicative of a disconnect between altered ECM and reduced endothelial cells, and known perfusion deficiencies present in PreT2D and T2D. This report supports that rising blood glucose values incite ECM remodeling and reduce SkM capillarization, and that targeting ECM would be a rational approach to improve health with metabolic disease.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00240.2020
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 309, No. 2 ( 2015-07-15), p. L129-L138
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 309, No. 2 ( 2015-07-15), p. L129-L138
    Abstract: Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans-signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 trans-signaling conditions 36 genes were upregulated, including PLA2G2A, IL13RA1, MUC1, and SOD2. Four genes, including CCL11, were downregulated at least twofold. The expression of 112 genes was divergent between IL-6 classical and trans-signaling, including the genes HILPDA, NNMT, DAB2, MUC1, WWC1, and VEGFA. Pathway analysis revealed that IL-6 trans-signaling induced expression of genes involved in regulation of airway remodeling, immune response, hypoxia, and glucose metabolism. Treatment of HASM cells with IL-6+sIL6R induced proliferation in a dose-dependent fashion, suggesting a role for IL-6 trans-signaling in asthma pathogenesis. These novel findings demonstrate differential effect of IL-6 trans-signaling on airway cells and identify IL-6 trans-signaling as a potential modifier of airway inflammation and remodeling.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00288.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Variable-length poly-C tract polymorphisms of the β 2 -adrenergic receptor 3′-UTR alter expression and agonist regulation
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 294, No. 2 ( 2008-02), p. L190-L195
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 294, No. 2 ( 2008-02), p. L190-L195
    Abstract: β 2 -Adrenergic receptors (β 2 -AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for β-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5′-flanking or coding region of the intronless β 2 -AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3′-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the β 2 -AR (Arg16) coding sequence followed by its 3′-UTR with the various polymorphic poly-C tracts. β 2 Arg16-11C had 25% lower mRNA expression and 33% lower β 2 -AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, β 2 Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with β 2 Arg16-12C and -13C. However, β 2 Arg16-12C underwent 50% less downregulation of receptor expression during β-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (β 2 Arg16-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (β 2 Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to β-agonist, and genotyping to identify these 3′-UTR polymorphisms may improve predictive power within the context of β 2 -AR haplotypes in pharmacogenetic studies.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00277.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma
    American Physiological Society ; 2007
    In:  Journal of Applied Physiology Vol. 103, No. 3 ( 2007-09), p. 1021-1029
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 103, No. 3 ( 2007-09), p. 1021-1029
    Abstract: Anemia may worsen neurological outcomes following traumatic brain injury (TBI) by undefined mechanisms. We hypothesized that hemodilutional anemia accentuates hypoxic cerebral injury following TBI. Anesthetized rats underwent unilateral TBI or sham injury ( n ≥ 7). Target hemoglobin concentrations between 50 and 70 g/l were achieved by exchanging 40–50% of the blood volume (1:1) with pentastarch. The effect of TBI, anemia, and TBI-anemia was assessed by measuring brain tissue oxygen tension (Pbr O 2 ), regional cerebral blood flow (rCBF), jugular venous oxygen saturation (Sjv O 2 ), cerebral contusion area, and nuclear staining for programmed cell death. Baseline postinjury Pbr O 2 values in the TBI and TBI-anemia groups (9.3 ± 1.3 and 11.3 ± 4.1 Torr, respectively) were lower than the uninjured controls (18.2 ± 5.2 Torr, P 〈 0.05 for both). Hemodilution caused a further reduction in Pbr O 2 in the TBI-anemia group relative to the TBI group without anemia (7.8 ± 2.7 vs. 14.8 ± 3.9 Torr, P 〈 0.05). The rCBF remained stable after TBI and increased comparably after hemodilution in both anemia and TBI-anemia groups. The Sjv O 2 was elevated after TBI (87.4 ± 8.9%, P 〈 0.05) and increased further following hemodilution (95.0 ± 1.6%, P 〈 0.05). Cerebral contusion area and nuclear counts for programmed cell death were increased following TBI-anemia (4.1 ± 3.0 mm 2 and 686 ± 192, respectively) relative to TBI alone (1.3 ± 0.3 mm 2 and 404 ± 133, respectively, P 〈 0.05 for both). Hemodilutional anemia reduced cerebral Pbr O 2 and oxygen extraction and increased cell death following TBI. These results support our hypothesis that acute anemia accentuated hypoxic cerebral injury after neurotrauma.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.01315.2006
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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