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Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue
Open accessAbstract
Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1alpha (HIF1alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1alpha, we determined that HIF1alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1alpha initiates adipose tissue fibrosis, with an associated increase in local inflammation. "Trichrome- and picrosirius red-positive streaks," enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1alpha and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by beta-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.
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In the citing paper
“Under conditions of over‐nutrition, chronic stress, and/or long periods of physical inactivity, maladaptive adipose tissue expansion causes an increase in hypoxia in these cells, because of their expanded size.[ 24 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [24]
In the citing paper
“HIF-1α activation is classically described as pro-angiogenic, but recent studies have shown it to also be pro-fibrotic and proinflammatory (4).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [4]
In the citing paper
“Interestingly, unlike acute AT expansion, the hypoxia response of obese ob/ob mice fails to induce VEGF expression, and instead a decrease in vascular density is observed (4).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [4]
In the citing paper
“Genetic introduction of dominant-active HIF-1α in mice was unable to induce an angiogenic response but instead increased the expression of several fibrotic genes (4).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [4]
In the citing paper
“merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages;”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“Moreover, we did not detect any increases in key components of the angiogenic or anaerobic glycolytic programs (4).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“Collectively, our results suggest that hypoxia-induced fibrosis in AT may be a key factor that ultimately stimulates the local inflammatory responses.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“As the result of this aberrant HIF-mediated transcriptional program, we proposed that the ECM in white AT accumulates fibrillar collagens; the upregulation of ECM thus causes local fibrosis.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“To investigate the effects of HIF-1α in white AT, we analyzed a transgenic mouse model in which we overexpressed a dominant active (degradation-resistant) deletion mutant of HIF-1α (HIF-1α-ΔODD) specifically in adipocytes (4).Unexpectedly, our model failed to induce any classical HIF-1α targets, such as VEGF-A.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“The most striking alteration we observed in this model was an enhanced fibrotic response, which included an upregulation lysyl oxidase (LOX), elastin, collagens I and III, tissue inhibitor of metalloproteinase I, and connective tissue growth factor.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“Compared to brown AT, white AT is not particularly well vascularized (4,20)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“this consequently leads to an acute hypoxic response within the adipocytes themselves (4)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
In the citing paper
“We have also shown that exposure to a HFD for merely a few days results in a significant increase in adipocyte cell size”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [4]
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Metadata
- Authors
- 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., Brekken, R. A., & Scherer, P. E.
- Affiliations
- University of Copenhagen (DK)
- Albert Einstein College of Medicine (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Touchstone Diabetes Center, Department of Internal Medicine
- University of Wisconsin–Madison (US)
- The Ohio State University (US)
- Hamon Center for Therapeutic Oncology and Division of Surgical Oncology
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Scherer, Philipp E.
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-08
- Volume
- 29
- Issue
- 16
- Pages
- 4467-4483
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2725728
- OpenAlex
- W2145323170
- Semantic Scholar
- 3bb117eb23d88a302c07f3497fedf4404f35dc4a
- Cited by
- 896
- References
- 56
- Citations by year
- 2026: 42 · 2025: 41 · 2024: 50 · 2023: 43 · 2022: 81 · 2021: 62 · 2020: 71 · 2019: 47 · 2018: 62 · 2017: 53 · 2016: 59 · 2015: 54 · 2014: 55 · 2013: 61 · 2012: 51
- FWCI
- 25.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA112023)
- National Institute of Diabetes and Digestive and Kidney Diseases (PL1DK081182, R01DK055758)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- hypoxia-inducible factor-1α, adipose tissue fibrosis, insulin resistance, adipose tissue hypoxia, obesity, lysyl oxidase, collagen cross-linking, adipose tissue inflammation, transgenic overexpression, adipose tissue dysfunction
- MeSH terms
- Animals, Hypoxia, Blood Glucose, Enzyme Inhibitors, Fibrosis, Gene Expression Regulation, Multigene Family, Glucose Tolerance Test, Humans, Insulin Resistance, Lipoxygenase, Mice, Obese, Mice, Transgenic, Molecular Sequence Data, Obesity, Transcription, Genetic, Neovascularization, Physiologic, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Adipose Tissue, White
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