Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*
Open accessAbstract
Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.
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Local hypoxia is a potent stimulus for new blood vessel formation through pro-angiogenic actions of HIF-1α and HIF-2α.
“Local hypoxia is a potent stimulus for new blood vessel formation through the pro-angiogenic actions of HIF-1α and HIF-2α (24,25).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [24]
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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
Identification and Importance of Brown Adipose Tissue in Adult Humans
Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y.-H., Doria, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810780 · Cited by 4,399 · 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
Cold-Activated Brown Adipose Tissue in Healthy Men
van Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M. A. F. L., Kemerink, G. J., Bouvy, N. D., Schrauwen, P., & Teule, G. J. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808718 · Cited by 3,452 · see citing works
Functional Brown Adipose Tissue in Healthy Adults
Virtanen, K. A., Lidell, M. E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N.-J., Enerbäck, S., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808949 · Cited by 3,058 · see citing works
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · see citing works
PRDM16 controls a brown fat/skeletal muscle switch
Seale, P., Bjork, B., Yang, W., Kajimura, S., Chin, S., Kuang, S., Scimè, A., Devarakonda, S., Conroe, H. M., Erdjument-Bromage, H., et al. (2008) · Nature · doi:10.1038/nature07182 · Cited by 2,347 · 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
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,638 · see citing works
Towards a molecular understanding of adaptive thermogenesis
Lowell, B. B., & Spiegelman, B. M. (2000) · Nature · doi:10.1038/35007527 · Cited by 1,630 · 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
Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis
Rajala, M. W., & Scherer, P. E. (2003) · Endocrinology · doi:10.1210/en.2003-0580 · Cited by 1,190 · see citing works
Cancello, R., Henegar, C., Viguerie, N., Taleb, S., Poitou, C., Rouault, C., Coupaye, M., Pelloux, V., Hugol, D., Bouillot, J.-L., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2277 · Cited by 1,164 · see citing works
New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure
Tseng, Y.-H., Kokkotou, E., Schulz, T. J., Huang, T. L., Winnay, J. N., Taniguchi, C. M., Tran, T. T., Suzuki, R., Espinoza, D. O., Yamamoto, Y., et al. (2008) · Nature · doi:10.1038/nature07221 · Cited by 1,099 · see citing works
Development of obesity in transgenic mice after genetic ablation of brown adipose tissue
Lowell, B. B., S-Susulic, V., Hamann, A., Lawitts, J. A., Himms-Hagen, J., Boyer, B. B., Kozak, L. P., & Flier, J. S. (1993) · Nature · doi:10.1038/366740a0 · Cited by 1,075 · see citing works
Kamei, N., Tobe, K., Suzuki, R., Ohsugi, M., Watanabe, T., Kubota, N., Ohtsuka-Kowatari, N., Kumagai, K., Sakamoto, K. Q., Kobayashi, M., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601284200 · Cited by 918 · see citing works
Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue
Halberg, N., Khan, T., Trujillo, M. E., Wernstedt-Asterholm, I., Attie, A. D., Sherwani, S., Wang, Z. V., Landskroner-Eiger, S., Dineen, S., Magalang, U. J., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00192-09 · Cited by 896 · 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
Angiogenesis modulates adipogenesis and obesity
Cao, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32239 · Cited by 736 · 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
Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?
Trayhurn, P., Wang, B., & Wood, I. S. (2008) · British Journal of Nutrition · doi:10.1017/s0007114508971282 · Cited by 464 · see citing works
The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease
Giaccia, A. J., Simon, M. C., & Johnson, R. (2004) · Genes & Development · doi:10.1101/gad.1243304 · Cited by 380 · 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
Xu, A., Lam, M. C., Chan, K. W., Wang, Y., Zhang, J., Hoo, R. L. C., Xu, J. Y., Chen, B., Chow, W.-S., Tso, A. W. K., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408452102 · Cited by 315 · see citing works
Self-citationHypoxia decreases insulin signaling pathways in adipocytes.
Regazzetti, C., Peraldi, P., Grémeaux, T., Najem-Lendom, R., Ben-Sahra, I., Cormont, M., Bost, F., Le Marchand-Brustel, Y., Tanti, J.-F., & Giorgetti-Peraldi, S. (2009) · Diabetes · doi:10.2337/db08-0457 · Cited by 281 · see citing works
Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans
Mehta, R., Steinkraus, K. A., Sutphin, G. L., Ramos, F. J., Shamieh, L. S., Huh, A., Davis, C., Chandler-Brown, D. B., & Kaeberlein, M. R. (2009) · Science · doi:10.1126/science.1173507 · Cited by 243 · see citing works
Chen, B., Lam, K. S. L., Wang, Y., Wu, D., Lam, M. C., Shen, J., Wong, L., Hoo, R. L. C., Zhang, J., & Xu, A. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.01.004 · Cited by 238 · see citing works
Self-citationAngiogenesis and development of adipose tissue
Christiaens, V., & LIJNEN, H. R. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.08.006 · Cited by 234 · see citing works
Pang, C., Gao, Z., Yin, J., Zhang, J., Jia, W., & Ye, J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90296.2008 · Cited by 229 · see citing works
Hamann, A., Flier, J. S., & Lowell, B. B. (1996) · Endocrinology · doi:10.1210/endo.137.1.8536614 · Cited by 205 · see citing works
Fredriksson, J. M., Lindquist, J. M., Bronnikov, G. E., & Nedergaard, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.18.13802 · Cited by 183 · see citing works
Chen, J., Zhao, S., Nakada, K., Kuge, Y., Tamaki, N., Okada, F., Wang, J., 進藤, 正., Higashino, F., Takeda, K., et al. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63924-7 · Cited by 170 · see citing works
Mechanism of enhanced lipolysis in adipose tissue of exercise-trained rats
Bukowiecki, L. J., Lupien, J., Folléa, N., Paradis, A., Richard, D., & LeBlanc, J. (1980) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1980.239.6.e422 · Cited by 105 · see citing works
Valet, P., Grujić, D., Wade, J. M., Ito, M., Zingaretti, M. C., Soloveva, V., Ross, S. R., Graves, R. A., Cinti, S., Lafontan, M., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005210200 · Cited by 101 · see citing works
ASANO, A., Morimatsu, M., Nikami, H., Yoshida, T., & Saito, M. (1997) · Biochemical Journal · doi:10.1042/bj3280179 · Cited by 94 · see citing works
Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor
Hemmeryckx, B., van Bree, R., HOEF, B. V., Vercruysse, L., LIJNEN, H. R., & Verhaeghe, J. (2008) · Endocrinology · doi:10.1210/en.2007-1272 · Cited by 28 · see citing works
Transgenic Mice Expressing Lipoprotein Lipase in Adipose Tissue
Hensley, L. L., Ranganathan, G., Wagner, E. M., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304200200 · Cited by 26 · see citing works
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- Xu, A., Lam, M. C., Chan, K. W., Wang, Y., Zhang, J., Hoo, R. L., Xu, J. Y., Chen, B., Chow, W. S., Tso, A. W., and Lam, K. S. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 6086 -6091
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The 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
Lee, Y. S., Kim, J.-W., Osborne, O., Oh, D. Y., Sasik, R., Schenk, S., Chen, A., Chung, H., Murphy, A., Watkins, S. M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.012 · Cited by 598 · see citing works
Hypoxia-inducible factors and the regulation of lipid metabolism
Mylonis, I., Simos, G., & Paraskeva, E. (2019) · Cells · doi:10.3390/cells8030214 · Cited by 316 · 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
Matsuura, H., Ichiki, T., Inoue, E., Nomura, M., Miyazaki, R., Hashimoto, T., Ikeda, J., Takayanagi, R., Fong, G.-H., & Sunagawa, K. (2013) · Circulation · doi:10.1161/circulationaha.113.001742 · Cited by 77 · see citing works
HDAC in obesity: A critical insight
Nijhawan, P., Behl, T., Khullar, G., Pal, G., Kandhwal, M., & Goyal, A. (2020) · Obesity Medicine · doi:10.1016/j.obmed.2020.100212 · Cited by 13 · see citing works
- Authors
- Zhang, X., Lam, K. S. L., Ye, H., Chung, S. K., Zhou, M., Wang, Y., & Xu, A.
- Affiliations
- Fudan University (CN)
- University of Hong Kong (HK)
- Corresponding author
- Xu, Aimin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 285
- Issue
- 43
- Pages
- 32869-32877
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2963410
- OpenAlex
- W1975452261
- Cited by
- 112
- References
- 39
- Citations by year
- 2026: 2 · 2024: 9 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 3 · 2018: 11 · 2017: 14 · 2016: 5 · 2015: 5 · 2014: 10 · 2013: 15 · 2012: 7
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Victoria University Research Repository (Victoria University) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Natural Science Foundation of China
- University of Hong Kong
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- hypoxia-inducible factor-1α, adipose tissue, obesity, impaired glucose tolerance, insulin resistance, energy expenditure, brown adipose tissue, thermogenesis, mitochondrial biogenesis, angiogenesis, lipid droplets, mitochondrial density, high-fat diet, adipose tissue inflammation
- MeSH terms
- Animals, Adipose Tissue, Brown, Diet, Dietary Fats, Energy Metabolism, Gene Expression Regulation, Humans, Mice, Transgenic, Mitochondria, Neovascularization, Pathologic, Obesity, Organ Specificity, Adipocytes, Glucose Intolerance, Thermogenesis, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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