title: Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice.
abstract: OBJECTIVE
  Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity.
  
  
  METHODS
  Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks.
  
  
  RESULTS
  The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice.
  
  
  CONCLUSIONS
  Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively.
authors.affiliation: Department of Molecular Physiology and Biophysics; Department of Internal Medicine/Division of Diabetes, Endocrinology, and Metabolism; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center; VA Nebraska Western Iowa Health Care System, Omaha, NE. Electronic address: s.viswanathan@unmc.edu.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Saraswathi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ramnanan
authors.forename: Anson W
authors.initials: AW
authors.lastname: Wilks
authors.forename: Cyrus V
authors.initials: CV
authors.lastname: Desouza
authors.forename: Amy A
authors.initials: AA
authors.lastname: Eller
authors.forename: Ganesan
authors.initials: G
authors.lastname: Murali
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ramalingam
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Katie C
authors.initials: KC
authors.lastname: Coate
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D051545:Cyclooxygenase 1 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D059305:Diet, High-Fat; D004435:Eating; D005260:Female; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000201:enzymology / Q000209:etiology; D060888:Real-Time Polymerase Chain Reaction; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D015415:Biomarkers; D020738:Leptin; D051545:Cyclooxygenase 1
keywords: 3-hydroxy-3-methyl-glutaryl-CoA reductase; 4′,6-diamidino-2-phenylindole;F4/80, murine homologue of EGF-like module-containing mucin-like hormone receptor-like 1; AMPK; AT; BMT; CC chemokine receptor-2; CC chemokine receptor-5; CCR2; CCR5; CD68; COX; COX-1 knock-out; COX-1+/+; COX-1−/−; CPT-1; DAPI; Dyslipidemia; Eicosanoids; FASN; FBP-1; G6PC; GAPDH; GC/MS; GSK; Glut-4; HMGCR; HOMA-IR; Hyperglycemia; IL; IR-β; L-FABP; LDLR; MCP-1; MGL; MIP-1α; MMP-12; NMR; Obesity; PCK-1 and PEPCK; PCX; PG; SAA-3; SGLT-2; SVC; TLR4; TNFα; TX; adenosine monophosphate-activated protein kinase; adipose tissue; apoE; apolipoprotein E; bone marrow transplantation; carnitine palmitoyl transferase-1; cluster of differentiation 68; cyclooxygenase; fatty acid synthase; fructose 1,6 bisphosphatase; gas chromatography/mass spectrometry; glucose transporter-4; glucose-6-phosphatase; glyceraldehyde 3 phosphate dehydrogenase; glycogen synthase kinase; homeostasis model assessment of insulin resistance; interleukin; liver fatty acid binding protein; low density lipoprotein receptor; macrophage galactose type lectin; macrophage inflammatory protein-1α; matrix metalloproteinase-12; monocyte chemoattractant protein; nuclear magnetic resonance; phospho insulin receptor beta; phosphoenol pyruvate carboxykinase; prostaglandin; pyruvate carboxylase; serum amyloid A-3; sodium glucose cotransporter-2; stromal vascular cells; thromboxane; toll-like receptor 4; tumor necrosis factor alpha; wild type