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Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity
Open accessAbstract
Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.
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“In insulin responsive tissues, sustained HIF-1 activation promotes a shift toward glycolytic metabolism, alters mitochondrial function, and contributes to insulin resistance by disrupting normal oxidative metabolism and redox balance [236,237].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [236]
Experimental — accuracy not yet measuredIn the citing paper
“Adipocytes respond by inducing glycolysis and angiogenesis in an attempt to alleviate the hypoxia (3).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [3]
In the citing paper
“For example, VEGF is upregulated in AT of mice fed a HFD for three days, but there are reports of both enhanced and reduced VEGF expression in chronic obesity (3,13,43,44), suggesting that sprouting angiogenesis is activated early and may or may not persist.”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [3]
In the citing paper
“In contrast, HIF-2α attenuates HFD-induced inflammation (3).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [3]
In the citing paper
“Within three days of HFF, rapid adipocyte hypertrophy along with mitochondrial uncoupling increase the demand for oxygen and reduce oxygen availability (3).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [3]
In the citing paper
“Although HIF-1α and HIF-2α pathways can interact, HIF-1α signaling dominates in obesity, playing a causative role in early AT dysfunction (3).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [3]
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Metadata
- Authors
- Lee, Y. S., Kim, J.-W., Osborne, O., Oh, D. Y., Sasik, R., Schenk, S., Chen, A., Chung, H., Murphy, A., Watkins, S. M., Quehenberger, O., Johnson, R. S., & Olefsky, J. M.
- Affiliations
- University of California San Diego (US)
- University of Cambridge (GB)
- Corresponding author
- Johnson, Randall S.
- Olefsky, Jerrold M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 6
- Pages
- 1339-1352
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4114226
- OpenAlex
- W2023289992
- Cited by
- 598
- References
- 51
- Citations by year
- 2026: 45 · 2025: 51 · 2024: 59 · 2023: 64 · 2022: 65 · 2021: 70 · 2020: 57 · 2019: 37 · 2018: 39 · 2017: 39 · 2016: 34 · 2015: 27 · 2014: 11
- FWCI
- 27.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging
- Wellcome Trust
- National Institutes of Health (DK-074868, P01-DK054441, DK-063491, DK-033651)
- National Institute of Child Health and Human Development (R01AG043120, R24HD050837)
- American Diabetes Association
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- HIF-1α, adipose tissue hypoxia, adipose tissue inflammation, insulin resistance, obesity, high-fat diet, uncoupled respiration, ANT2, saturated fatty acids, mitochondrial respiration, glucose tolerance
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Fatty Acids, Inflammation, Insulin Resistance, Nitric Oxide, Obesity, Oxygen, Cell Hypoxia, Adipocytes, Mice, Knockout, Lactic Acid, Adenine Nucleotide Translocator 2, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Diet, High-Fat
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