Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity
Vincenza Cifarelli, … , Bruce W. Patterson, Samuel Klein
Vincenza Cifarelli, … , Bruce W. Patterson, Samuel Klein
Published November 9, 2020
Citation Information: J Clin Invest. 2020;130(12):6688-6699. https://doi.org/10.1172/JCI141828.
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Clinical Medicine Metabolism

Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity

Abstract

BACKGROUND Data 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.METHODS We 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).RESULTS AT 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.CONCLUSION These 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 REGISTRATION ClinicalTrials.gov NCT02706262.FUNDING This 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.

Authors

Vincenza Cifarelli, Scott C. Beeman, Gordon I. Smith, Jun Yoshino, Darya Morozov, Joseph W. Beals, Brandon D. Kayser, Jeramie D. Watrous, Mohit Jain, Bruce W. Patterson, Samuel Klein

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Figure 9

Proposed effects of decreased AT oxygen tension on AT biology and insulin sensitivity in people with obesity.

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Proposed effects of decreased AT oxygen tension on AT biology and insuli...
An increase in AT mass associated with obesity decreases AT pO2, which increases AT HIF-1α expression and triggers a cascade of alterations in AT biology, including a decrease in BCAA catabolism and an increase in inflammation and fibrosis. These changes lead to an increase in circulating BCAAs and PAI-1 that impair systemic insulin action. Differences in AT pO2 among people with obesity provide a potential mechanism to help explain the differences in insulin sensitivity between people with metabolically healthy and metabolically unhealthy obesity.