Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation
Open accessAbstract
Background—: Adipose tissue (AT) dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes mellitus and cardiovascular disease. Recent in vitro studies suggest that AT hypoxia may induce inflammation. We hypothesized that adipose tissue blood flow (ATBF) regulates AT oxygen partial pressure (AT P o 2 ), thereby affecting AT inflammation and insulin sensitivity. Methods and Results—: We developed an optochemical measurement system for continuous monitoring of AT P o 2 using microdialysis. The effect of alterations in ATBF on AT P o 2 was investigated in lean and obese subjects with both pharmacological and physiological approaches to manipulate ATBF. Local administration of angiotensin II (vasoconstrictor) in abdominal subcutaneous AT decreased ATBF and AT P o 2 , whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT P o 2 in lean subjects, but these responses were blunted in obese individuals. However, AT P o 2 was higher (hyperoxia) in obese subjects despite lower ATBF, which appears to be explained by lower AT oxygen consumption. This was accompanied by insulin resistance, lower AT capillarization, lower AT expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher AT gene expression of macrophage infiltration and inflammatory markers. Conclusions—: Our findings establish ATBF as an important regulator of AT P o 2 . Nevertheless, obese individuals exhibit AT hyperoxia despite lower ATBF, which seems to be explained by lower AT oxygen consumption. This is accompanied by insulin resistance, impaired AT capillarization, and higher AT gene expression of inflammatory cell markers. Clinical Trial Registration—: URL: http://www.trialregister.nl . Unique identifier: NTR2451.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Cites
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.3.e214 · Cited by 7,425 · 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
Increased oxidative stress in obesity and its impact on metabolic syndrome
Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., Nakayama, O., Makishima, M., Matsuda, M., & Shimomura, I. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21625 · Cited by 5,508 · see citing works
Inflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143 · see citing works
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · see citing works
TLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · see citing works
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · see citing works
Adipokines: inflammation and the pleiotropic role of white adipose tissue
Trayhurn, P., & Wood, I. S. (2004) · British Journal of Nutrition · doi:10.1079/bjn20041213 · Cited by 2,210 · see citing works
Adipose Tissue, Inflammation, and Cardiovascular Disease
Berg, A. H., & Scherer, P. E. (2005) · Circulation Research · doi:10.1161/01.res.0000163635.62927.34 · Cited by 2,113 · see citing works
Molecular mediators of hepatic steatosis and liver injury
Browning, J. D., & Horton, J. D. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422422 · Cited by 1,772 · see citing works
Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation
Hosogai, N., Fukuhara, A., Oshima, K., Miyata, Y., Tanaka, S., Segawa, K., Furukawa, S., Tochino, Y., Komuro, R., Matsuda, M., et al. (2007) · Diabetes · doi:10.2337/db06-0911 · Cited by 1,257 · 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
HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α
Arany, Z., Foo, S.-Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., et al. (2008) · Nature · doi:10.1038/nature06613 · Cited by 1,054 · see citing works
Adipose tissue mass can be regulated through the vasculature
Rupnick, M. A., Panigrahy, D., Zhang, C.-Y., Dallabrida, S. M., Lowell, B. B., Langer, R., & Folkman, M. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162349799 · Cited by 845 · see citing works
Ye, J., Gao, Z., Yin, J., & He, Q. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00435.2007 · Cited by 840 · see citing works
Reduced Adipose Tissue Oxygenation in Human Obesity
Pasarica, M., Sereda, O. R., Redman, L. M., Albarado, D. C., Hymel, D. T., Roan, L. E., Rood, J. C., Burk, D. H., & Smith, S. R. (2009) · Diabetes · doi:10.2337/db08-1098 · Cited by 786 · see citing works
Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone.
Wilson-Fritch, L., Nicoloro, S., Chouinard, M., Lazar, M. A., Chui, P. C., Leszyk, J., Straubhaar, J., Czech, M. P., & Corvera, S. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21752 · Cited by 616 · see citing works
The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance
Goossens, G. H. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.10.010 · Cited by 591 · see citing works
Self-citationRausch, M. E., Weisberg, S., Vardhana, P., & Tortoriello, D. V. (2008) · International Journal of Obesity · doi:10.1038/sj.ijo.0803744 · Cited by 585 · see citing works
Emerging role of adipose tissue hypoxia in obesity and insulin resistance
Ye, J. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.229 · Cited by 539 · see citing works
Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals
Nisoli, E., Falcone, S., Tonello, C., Cozzi, V., Palomba, L., Fiorani, M., Pisconti, A., Brunelli, S., Cardile, A., Francolini, M., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405432101 · Cited by 495 · see citing works
Adipose tissue angiogenesis1,2
Hausman, G., & Richardson, R. L. (2004) · Journal of Animal Science · doi:10.2527/2004.823925x · Cited by 417 · see citing works
Hypoxia-Independent Angiogenesis in Adipose Tissues during Cold Acclimation
Xue, Y., Petrovič, N., Cao, R., Larsson, O. S., Lim, S., Chen, S., Feldmann, H. M., Liang, Z., Zhu, Z., Nedergaard, J., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.11.009 · Cited by 379 · see citing works
Obesity Decreases Perioperative Tissue Oxygenation
Kabon, B., Nagele, A., Reddy, D., Eagon, C., Fleshman, J. W., Sessler, D. I., & Kurz, A. (2004) · Anesthesiology · doi:10.1097/00000542-200402000-00015 · Cited by 376 · see citing works
Rong, J. X., Qiu, Y., Hansen, M. K., Zhu, L., Zhang, V., Xie, M., Okamoto, Y., Mattie, M. D., Higashiyama, H., Asano, S., et al. (2007) · Diabetes · doi:10.2337/db06-1135 · Cited by 335 · see citing works
TNF- downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
Valerio, A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28570 · Cited by 327 · see citing works
Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice
Bråkenhielm, E., Cao, R., Gao, B., Angelin, B., Cannon, B., Parini, P., & Cao, Y. (2004) · Circulation Research · doi:10.1161/01.res.0000132745.76882.70 · Cited by 326 · see citing works
Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes
Lolmède, K., Durand de Saint Front, V, Galitzky, J., Lafontan, M., & Bouloumié, A. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802407 · Cited by 224 · see citing works
O’Hagan, K., Cocchiglia, S., Zhdanov, A. V., Tambuwala, M. M., Cummins, E. P., Monfared, M. M., Agbor, T. A., Garvey, J., Papkovsky, D. B., Taylor, C. T., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808801106 · Cited by 191 · see citing works
Karpe, F., Fielding, B. A., Ilic, V., Macdonald, I. A., Summers, L. K. M., & Frayn, K. N. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2467 · Cited by 177 · see citing works
Blaak, E. E., van Baak, M. A., Kemerink, G. J., Pakbiers, M. T. W., Heidendal, G. A. K., & Saris, W. H. M. (1995) · Metabolism · doi:10.1016/0026-0495(95)90262-7 · Cited by 106 · see citing works
Self-citationBaicalin increases VEGF expression and angiogenesis by activating the ERR /PGC-1 pathway
Zhang, K., Lu, J., Mori, T., et al. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq296 · Cited by 105 · see citing works
Jansson, Larsson, & LÖnnroth (1998) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.1998.00360.x · Cited by 101 · see citing works
Respiration in Adipocytes is Inhibited by Reactive Oxygen Species
Wang, T., Si, Y., Shirihai, O. S., Si, H., Schultz, V., Corkey, R. F., Hu, L., Deeney, J. T., Guo, W., & Corkey, B. E. (2009) · Obesity · doi:10.1038/oby.2009.456 · Cited by 85 · see citing works
Goossens, G. H., Blaak, E. E., Saris, W. H. M., & van Baak, M. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032053 · Cited by 84 · see citing works
Self-citationEndocrine Role of the Renin-Angiotensin System in Human Adipose Tissue and Muscle
Goossens, G. H., Jocken, J. W. E., Blaak, E. E., Schiffers, P. M. H., Saris, W. H. M., & van Baak, M. A. (2007) · Hypertension · doi:10.1161/01.hyp.0000256091.55393.92 · Cited by 68 · see citing works
Self-citationSamra, J. S., Frayn, K. N., Giddings, J. A., Clark, M. L., & Macdonald, I. A. (1995) · Clinical Physiology · doi:10.1111/j.1475-097x.1995.tb00515.x · Cited by 60 · see citing works
de Villota, E. D., Carmona, M. T. G., RUBIO, J. J., et al. (1981) · British Journal of Anaesthesia · doi:10.1093/bja/53.12.1325 · Cited by 54 · see citing works
Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue
Hallgren, P., Sjöström, L., Hedlund, H., Lundell, L., & Olbe, L. C. (1989) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1989.256.4.e467 · Cited by 52 · see citing works
Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis
Bizzarri, A., Koehler, H., Čajlaković, M., Pasic, A., Schaupp, L. A., Klimant, I., & Ribitsch, V. (2006) · Analytica Chimica Acta · doi:10.1016/j.aca.2006.03.101 · Cited by 46 · see citing works
Self-citationAngiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans
Goossens, G. H., McQuaid, S., Dennis, A., van Baak, M. A., Blaak, E. E., Frayn, K. N., Saris, W. H. M., & Karpe, F. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2005.101352 · Cited by 44 · see citing works
Self-citationArdilouze, J., Karpe, F., Currie, J. M., Frayn, K. N., & Fielding, B. A. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802541 · Cited by 36 · see citing works
Transcriptional control of human adipose tissue blood flow
Perez‐Matute, P., Neville, M. J., Tan, G. D., Frayn, K. N., & Karpe, F. (2009) · Obesity · doi:10.1038/oby.2008.606 · Cited by 32 · see citing works
Defective brown adipose oxygen consumption in obese Zucker rats
Levin, B. E., Finnegan, M. B., Marquet, E., et al. (1984) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1984.247.1.e94 · Cited by 25 · see citing works
Schiffelers, S. L. H., Akkermans, J. A. P., Saris, W. H. M., & Blaak, E. E. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.802230 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The metabolic phenotype in obesity: Fat mass, body fat distribution, and adipose tissue function
Goossens, G. H. (2017) · Obesity Facts · doi:10.1159/000471488 · Cited by 8,481 · see citing works
Self-citationAdipose tissue inflammation and metabolic dysfunction in obesity
Kawai, T., Autieri, M. V., & Scalia, R. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00379.2020 · Cited by 1,947 · see citing works
Fibrosis and adipose tissue dysfunction.
Sun, K., Tordjman, J., Clément, K., & Scherer, P. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.016 · Cited by 960 · see citing works
Self-citationThe ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
Crewe, C., An, Y. A., & Scherer, P. E. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88883 · Cited by 732 · see citing works
What causes the insulin resistance underlying obesity?
Hardy, O. T., Czech, M. P., & Corvera, S. (2012) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3283514e13 · Cited by 563 · see citing works
Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2017 · Cited by 462 · see citing works
Obesity and the risk of cardiometabolic diseases
Valenzuela, P. L., Carrera-Bastos, P., Castillo-García, A., Lieberman, D. E., Santos-Lozano, A., & Lucia, A. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00847-5 · Cited by 452 · see citing works
Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity
Muir, L. A., Neeley, C. K., Meyer, K. A., Baker, N. A., Brosius, A. M., Washabaugh, A. R., Varban, O. A., Finks, J. F., Zamarron, B. F., Flesher, C. G., et al. (2016) · Obesity · doi:10.1002/oby.21377 · Cited by 367 · see citing works
Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity
Donath, M. Y., Dalmas, É., Sauter, N. S., & Böni-Schnetzler, M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.001 · Cited by 338 · see citing works
Keeley, T. P., & Mann, G. E. (2019) · Physiological Reviews · doi:10.1152/physrev.00041.2017 · Cited by 329 · 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
Mechanisms of weight regain after weight loss — the role of adipose tissue
van Baak, M. A., & Mariman, E. C. M. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0148-4 · Cited by 203 · see citing works
Hypoxia and Adipocyte Physiology: Implications for Adipose Tissue Dysfunction in Obesity
Trayhurn, P. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161156 · Cited by 194 · see citing works
Targeting fatty acid metabolism to improve glucose metabolism
Stinkens, R., Goossens, G. H., Jocken, J. W. E., & Blaak, E. E. (2015) · Obesity Reviews · doi:10.1111/obr.12298 · Cited by 183 · see citing works
Self-citationRoemeling-van Rhijn, M., Mensah, F. K. F., Korevaar, S. S., Leijs, M. J., van Osch, G. J. V. M., IJzermans, J. N. M., Betjes, M. G. H., Baan, C. C., Weimar, W., & Hoogduijn, M. J. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00203 · Cited by 150 · see citing works
Konings, E., Timmers, S., Boekschoten, M. V., Goossens, G. H., Jocken, J. W., Afman, L. A., Müller, M., Schrauwen, P., Mariman, E. C., & Blaak, E. E. (2014) · International Journal of Obesity · doi:10.1038/ijo.2013.155 · Cited by 143 · see citing works
Self-citationDecreased Adipose Tissue Oxygenation Associates with Insulin Resistance in Individuals with Obesity
Cifarelli, V., Beeman, S. C., Smith, G. I., Yoshino, J., Morozov, D., Beals, J. W., Kayser, B. D., Watrous, J. D., Jain, M., Patterson, B. W., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci141828 · Cited by 132 · see citing works
van Woerden, G., van Veldhuisen, D. J., Westenbrink, B. D., de Boer, R. A., Rienstra, M., & Gorter, T. M. (2022) · European Journal of Heart Failure · doi:10.1002/ejhf.2741 · Cited by 128 · see citing works
García-Martín, R., Alexaki, V. I., Qin, N., Rubín de Celis, M. F., Economopoulou, M., Ziogas, A., Gercken, B., Kotlabova, K., Phieler, J., Ehrhart-Bornstein, M., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00430-15 · Cited by 86 · see citing works
Niemeijer, V. M., Jansen, J. P., van Dijk, T., Spee, R. F., Meijer, E. J., Kemps, H. M. C., & Wijn, P. F. F. (2017) · Physiological Measurement · doi:10.1088/1361-6579/aa5dd5 · Cited by 61 · see citing works
Thomas, A., Belaidi, E., Aron-Wisnewsky, J., van der Zon, G. C., Levy, P., Clement, K., Pepin, J.-L., Godin-Ribuot, D., & Guigas, B. (2016) · Scientific Reports · doi:10.1038/srep24618 · Cited by 33 · see citing works
Demandt, J. A. F., Dubois, L. J., van Kuijk, K., Zaťovičová, M., Jin, H., Parkkila, S., van der Laan, S. W., Jelenska, L., Mees, B. M. E., Reutelingsperger, C. P. M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-020-79978-5 · Cited by 9 · see citing works
- Authors
- Goossens, G. H., Bizzarri, A., Venteclef, N., Essers, Y., Cleutjens, J. P., Konings, E., Jocken, J. W. E., Čajlaković, M., Ribitsch, V., Clément, K., & Blaak, E. E.
- Affiliations
- Joanneum Research (AT)
- ORCID
- Venue
- Circulation
- Published
- 2011-07-05
- Volume
- 124
- Issue
- 1
- Pages
- 67-76
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2127521961
- Cited by
- 324
- References
- 45
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 20 · 2023: 15 · 2022: 20 · 2021: 23 · 2020: 21 · 2019: 19 · 2018: 21 · 2017: 33 · 2016: 22 · 2015: 24 · 2014: 22 · 2013: 31 · 2012: 26
- FWCI
- 20.04
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- adipose tissue hypoxia, obesity, insulin resistance, mitochondrial biogenesis, angiotensin II, isoproterenol, glucose ingestion, macrophage infiltration, type 2 diabetes
- MeSH terms
- Adipose Tissue, Angiotensin II, Humans, Inflammation, Insulin Resistance, Isoproterenol, Male, Microcirculation, Middle Aged, Mitochondria, Obesity, Oxygen, Oxygen Consumption, Regional Blood Flow, Thinness, Vasoconstrictor Agents, Vasodilator Agents, Hyperoxia
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
