title: Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding.
abstract: OBJECTIVE
  Obesity is characterized by chronic inflammation of adipose tissue, which contributes to insulin resistance and diabetes. Although nitric oxide (NO) signaling has antiinflammatory effects in the vasculature, whether reduced NO contributes to adipose tissue inflammation is unknown. We sought to determine whether (1) obesity induced by high-fat (HF) diet reduces endothelial nitric oxide signaling in adipose tissue, (2) reduced endothelial nitric oxide synthase (eNOS) signaling is sufficient to induce adipose tissue inflammation independent of diet, and (3) increased cGMP signaling can block adipose tissue inflammation induced by HF feeding.
  
  
  RESULTS
  Relative to mice fed a low-fat diet, an HF diet markedly reduced phospho-eNOS and phospho-vasodilator-stimulated phosphoprotein (phospho-VASP), markers of vascular NO signaling. Expression of proinflammatory cytokines was increased in adipose tissue of eNOS-/- mice. Conversely, enhancement of signaling downstream of NO by phosphodiesterase-5 inhibition using sildenafil attenuated HF-induced proinflammatory cytokine expression and the recruitment of macrophages into adipose tissue. Finally, we implicate a role for VASP, a downstream mediator of NO-cGMP signaling in mediating eNOS-induced antiinflammatory effects because VASP-/- mice recapitulated the proinflammatory phenotype displayed by eNOS-/- mice.
  
  
  CONCLUSIONS
  These results imply a physiological role for endothelial NO to limit obesity-associated inflammation in adipose tissue and hence identify the NO-cGMP-VASP pathway as a potential therapeutic target in the treatment of diabetes.
authors: Department of Medicine, 815 Mercer St, University of Washington, Seattle, WA 98109, USA.
authors: Priya
authors: P
authors: Handa
authors: Sanshiro
authors: S
authors: Tateya
authors: Norma O
authors: NO
authors: Rizzo
authors: Andrew M
authors: AM
authors: Cheng
authors: Vicki
authors: V
authors: Morgan-Stevenson
authors: Chang-Yeop
authors: CY
authors: Han
authors: Alexander W
authors: AW
authors: Clowes
authors: Guenter
authors: G
authors: Daum
authors: Kevin D
authors: KD
authors: O'Brien
authors: Michael W
authors: MW
authors: Schwartz
authors: Alan
authors: A
authors: Chait
authors: Francis
authors: F
authors: Kim
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D004041:Dietary Fats; D008840:Microfilament Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010750:Phosphoproteins; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP