Decreased Adipose Tissue Oxygenation Associates with Insulin Resistance in Individuals with Obesity
Open accessAbstract
BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.
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Adipose tissue growth without adequate vascularization results in hypoxia.
“Adipose tissue growth without adequate vascularization results in hypoxia.”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [44]
Reduced adipose tissue oxygenation contributes to insulin resistance by decreasing branched-chain amino acid catabolism and increasing plasma branched-chain amino acid concentrations.
“Reduced adipose tissue oxygenation contributes to IR by decreasing branched-chain amino acid catabolism and increasing plasma branched-chain amino acid concentrations [44].”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [44]
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Bednarz, K., Kowalczyk, K., Cwynar, M., Czapla, D., Czarkowski, W., Kmita, D., Nowak, A., & Madej, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084334 · Cited by 148 · see citing works
Adipose–Muscle Crosstalk in Age-Related Metabolic Disorders: The Emerging Roles of Adipo-Myokines
Fang, P., She, Y., Yu, M., Min, W., Shang, W., & Zhang, Z. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101829 · Cited by 62 · see citing works
Frankowski, R., Kobierecki, M., Wittczak, A., Różycka-Kosmalska, M., Pietras, T., Sipowicz, K., & Kosmalski, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119677 · Cited by 58 · see citing works
- Authors
- 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., & Klein, S.
- Affiliations
- Washington University in St. Louis (US)
- University of California San Diego (US)
- Corresponding author
- Klein, Samuel
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2020-11-09
- Volume
- 130
- Issue
- 12
- Pages
- 6688-6699
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7685757
- OpenAlex
- W3101109668
- Cited by
- 132
- References
- 82
- Citations by year
- 2026: 18 · 2025: 14 · 2024: 33 · 2023: 25 · 2022: 22 · 2021: 18 · 2020: 1 · 2012: 1
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK109119,K01DK116917,DK56341,DK20579,DK052574)
- National Heart, Lung, and Blood Institute (T32HL130357)
- National Institute of Environmental Health Sciences (R01ES027595,P42ES010337)
- Foundation for Barnes-Jewish Hospital (N/A)
- National Center for Research Resources (S10RR0227552,S10OD020025,S10OD026929,UL1TR002345)
- 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
- insulin resistance, obesity, metabolically healthy obesity, metabolically unhealthy obesity, insulin sensitivity, branched-chain amino acid catabolism, plasminogen activator inhibitor-1, adipose tissue inflammation, adipose tissue fibrosis, adipose tissue gene expression, hepatic insulin sensitivity, whole-body insulin sensitivity
- MeSH terms
- Adult, Amino Acids, Branched-Chain, Female, Gene Expression Regulation, Humans, Inflammation, Insulin Resistance, Male, Obesity, Oxygen, Biomarkers, Subcutaneous Fat
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