Reduced vascular nitric oxide–cGMP signaling contributes to adipose tissue inflammation during high-fat feeding
Open accessAbstract
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. METHODS AND 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Selective overexpression of NOS2 in liver is sufficient to cause hepatic insulin resistance, hyperglycemia, and hyperinsulinemia.
“Selective overexpression of NOS2 in liver is sufficient to cause hepatic insulin resistance, hyperglycemia and hyperinsulinemia [355]”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [355]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760 · see citing works
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29881 · Cited by 4,664 · see citing works
Macrophages, inflammation, and insulin resistance
Olefsky, J. M., & Glass, C. K. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135846 · Cited by 2,733 · see citing works
Chen, H., Charlat, O., Tartaglia, L. A., Woolf, E. A., Weng, X., Ellis, S. J., Lakey, N. D., Culpepper, J., More, K. J., Breitbart, R. E., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81294-5 · Cited by 2,214 · see citing works
Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide
Nisoli, E., Clementi, E., Paolucci, C., Cozzi, V., Tonello, C., Sciorati, C., Bracale, R., Valerio, A., Francolini, M., Moncada, S., et al. (2003) · Science · doi:10.1126/science.1079368 · Cited by 1,243 · see citing works
Obesity, inflammation, and atherosclerosis
Rocha, V. Z., & Libby, P. (2009) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2009.55 · Cited by 994 · see citing works
Serafini, P., Meckel, K. F., Kelso, M., Noonan, K. A., Califano, J. A., Koch, W. M., Dolcetti, L., Bronte, V., & Borrello, I. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061104 · Cited by 767 · see citing works
Alternative macrophage activation and metabolism
Odegaard, J. I., & Chawla, A. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130138 · Cited by 640 · see citing works
Metabolic syndrome and cardiovascular disease
Qiao, Q., Gao, W., Zhang, L., Nyamdorj, R., & Tuomilehto, J. O. (2007) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/000456307780480963 · Cited by 375 · see citing works
Kim, F., Pham, M., Maloney, E., Rizzo, N. O., Morton, G. J., Wisse, B. E., Kirk, E. A., Chait, A., & Schwartz, M. W. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.169722 · Cited by 364 · see citing works
Self-citationeNOS, metabolic syndrome and cardiovascular disease
Huang, P. L. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.03.005 · Cited by 357 · see citing works
Ozaki, M., Kawashima, S., Yamashita, T., Hirase, T., Namiki, M., Inoue, N., Hirata, K., Yasui, H., Sakurai, H., Yoshida, Y., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15215 · Cited by 312 · see citing works
Ozaki, M., Kawashima, S., Yamashita, T., Hirase, T., Namiki, M., Inoue, N., Hirata, K.-I., Yasui, H., Sakurai, H., Yoshida, Y., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215215 · Cited by 268 · see citing works
Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism
Champion, H. C., Bivalacqua, T. J., Takimoto, E., Kass, D. A., & Burnett, A. L. “. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407183102 · Cited by 258 · see citing works
Mechanisms of obesity and related pathologies: The macro‐ and microcirculation of adipose tissue
Rutkowski, J. M., Davis, K. E., & Scherer, P. E. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07303.x · Cited by 254 · see citing works
Oelze, M. W., Mollnau, H., Hoffmann, N., Warnholtz, A., Bodenschatz, M., Smolenski, A., Walter, U., Skatchkov, M. P., Meinertz, T., & Münzel, T. F. (2000) · Circulation Research · doi:10.1161/01.res.87.11.999 · Cited by 253 · see citing works
Liu, V. W. T., & Huang, P. L. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.06.024 · Cited by 252 · see citing works
Ayala, J. E., Bracy, D. P., Julien, B. M., Rottman, J. N., Fueger, P. T., & Wasserman, D. H. (2007) · Diabetes · doi:10.2337/db06-0883 · Cited by 237 · see citing works
Nitric Oxide Regulates Monocyte Chemotactic Protein-1
Tsao, P. S., Wang, B., Buitrago, R., Shyy, J. Y.-J., & Cooke, J. P. (1997) · Circulation · doi:10.1161/01.cir.96.3.934 · Cited by 218 · see citing works
Kirk, E. A., Sagawa, Z. K., McDonald, T. O., O'Brien, K. D., & Heinecke, J. W. (2008) · Diabetes · doi:10.2337/db07-1061 · Cited by 149 · see citing works
Self-citationAversa, A., Vitale, C., Volterrani, M., Fabbri, A., Spera, G., Fini, M., & Rosano, G. M. C. (2008) · Diabetic Medicine · doi:10.1111/j.1464-5491.2007.02298.x · Cited by 132 · see citing works
The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue
Surmi, B. K., & Hasty, A. H. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.12.004 · Cited by 129 · see citing works
Cytoskeleton assembly at endothelial cell–cell contacts is regulated by αII-spectrin–VASP complexes
Benz, P. M., Blume, C., Moebius, J., Oschatz, C., Schuh, K., Sickmann, A., Walter, U., Feller, S. M., & Renné, T. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200709181 · Cited by 116 · see citing works
A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression
Takaya, T., Hirata, K., Yamashita, T., Shinohara, M., Sasaki, N., Inoue, N., Yada, T., Goto, M., Fukatsu, A., Hayashi, T., et al. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.142182 · Cited by 102 · see citing works
Rizzo, N. O., Maloney, E., Pham, M., Luttrell, I., Wessells, H., Tateya, S., Daum, G., Handa, P., Schwartz, M. W., & Kim, F. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.199893 · Cited by 98 · see citing works
Self-citationChen, L., Daum, G., Chitaley, K., Coats, S. A., Bowen‐Pope, D. F., Eigenthaler, M., Thumati, N. R., Walter, U., & Clowes, A. W. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000134705.39654.53 · Cited by 93 · see citing works
Self-citationSildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway
Senthilkumar, A., Smith, R. D., Khitha, J., Arora, N., Veerareddy, S., Langston, W., Chidlow, J. H., Barlow, S. C., Teng, X., Patel, R. P., et al. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.147421 · Cited by 91 · see citing works
Nitric oxide promotes differentiation of rat white preadipocytes in culture
Yan, H., Aziz, E., Shillabeer, G., Wong, A., Shanghavi, D. S., Kermouni, A., Abdel-Hafez, M., & Lau, D. C. W. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200305-jlr200 · Cited by 89 · see citing works
Relaxing the actin cytoskeleton for adhesion and movement with Ena/VASP
Trichet, L., Sykes, C., & Plastino, J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200710168 · Cited by 77 · see citing works
Schäfer, A., Fraccarollo, D., Pförtsch, S., Flierl, U., Vogt, C., Pfrang, J., Kobsar, A. L., Renné, T., Eigenthaler, M., Ertl, G., et al. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707459 · Cited by 74 · see citing works
Russo, I., Mese, P. D., Doronzo, G., Mattiello, L., Viretto, M., Bosìa, A., Anfossi, G., & Trovati, M. (2007) · Endocrinology · doi:10.1210/en.2007-0920 · Cited by 47 · see citing works
Nikolic, D. M., Li, Y., Liu, S., & Wang, S. (2011) · Obesity · doi:10.1038/oby.2010.223 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Redox control of inflammation in macrophages
Brüne, B., Dehne, N., Grossmann, N., Jung, M., Namgaladze, D., Schmid, T., von Knethen, A., & Weigert, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4785 · Cited by 377 · see citing works
Regulation of obesity and insulin resistance by nitric oxide
Sansbury, B. E., & Hill, B. G. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.05.016 · Cited by 274 · see citing works
Endothelial dysfunction in obesity
Engin, A. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_15 · Cited by 255 · see citing works
Recent advances in obesity-induced inflammation and insulin resistance
Tateya, S., Kim, F., & Tamori, Y. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00093 · Cited by 211 · see citing works
Self-citation
- Authors
- Handa, P., Tateya, S., Rizzo, N. O., Cheng, A. M., Morgan-Stevenson, V., Han, C.-Y., Clowes, A. W., Daum, G., O'Brien, K. D., Schwartz, M. W., Chait, A., & Kim, F.
- Affiliations
- University of Washington (US)
- From the Department of Medicine (P.H., S.T., N.O.R., A.M.C., V.M.-S., C.-Y.H., K.D.O., M.W.S., A.C., F.K.), Department of Surgery (A.W.C., G.D.), and Diabetes and Obesity Center of Excellence (P.H., S.T., N.O.R., A.M.C., V.M.-S., C.-Y.H., M.W.S., A.C., F.K.), University of Washington, Seattle, WA.
- Venue
- Arteriosclerosis Thrombosis and Vascular Biology
- Published
- 2011-12
- Volume
- 31
- Issue
- 12
- Pages
- 2827-2835
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC3342311
- OpenAlex
- W2121689427
- Cited by
- 86
- References
- 33
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 1 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 7
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01dk073878-05)
- National Heart, Lung, and Blood Institute (HL-52459, P01HL092969, HL94352, R56HL094352, HL92969, R01HL052459, R01HL094352, R37HL052459)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-083042, DK052989, R01DK052989, R01-DK-073878, DK-073878, R01DK090320, P30DK035816, R01DK083042)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- nitric oxide signaling, cGMP signaling, adipose tissue inflammation, endothelial nitric oxide synthase, VASP, high-fat diet, obesity, inflammatory cytokines, macrophage recruitment, phosphodiesterase-5 inhibition, sildenafil, diabetes mellitus, insulin resistance
- MeSH terms
- Sildenafil Citrate, Vasodilator-Stimulated Phosphoprotein, Adipose Tissue, Animals, Dietary Fats, Disease Models, Animal, Endothelium, Vascular, Cyclic GMP, Inflammation, Insulin Resistance, Male, Mice, Inbred C57BL, Microfilament Proteins, Nitric Oxide, Obesity, Phosphoproteins, Phosphorylation, Piperazines, Purines, Sulfones, Signal Transduction, Cell Adhesion Molecules, Mice, Knockout, Mice, Nitric Oxide Synthase Type III, Phosphodiesterase 5 Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
