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 Research and Public Health 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 2

AT oxygen tension is reduced in MUO and is positively associated with insulin sensitivity.

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AT oxygen tension is reduced in MUO and is positively associated with in...
(A and B) AT oxygen partial pressure (AT pO2) (A) and HIF1A gene expression (B) in metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20) groups. Data are means ± SEM. One-way ANOVA and Fisher’s least significant difference procedure were used to identify significant mean differences between groups. *Value significantly different from the MHL value, P < 0.001. †Value significantly different from the MHO value, P < 0.05. #Linear trend, P < 0.001. (C and D) Relationship between AT pO2 and hepatic insulin sensitivity index (HISI), assessed as 1000 divided by the product of endogenous glucose rate of appearance (in μmol/kg fat-free mass/min) and plasma insulin concentration (in μU/mL) in the overnight fasting state (C), and between pO2 and whole-body insulin sensitivity, assessed as glucose rate of disposal (Rd; in nmol/kg fat-free mass/min) divided by plasma insulin (I) concentration (in μU/mL) during a hyperinsulinemic-euglycemic clamp procedure (D), in MHL (white circles; n = 11), MHO (gray circles; n = 15), and MUO (black circles; n = 20) participants. Associations between AT pO2 and HISI and between AT pO2 and glucose Rd/I were determined using Pearson’s correlation coefficient.