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.
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
Submitter: Gijs H. Goossens | G.Goossens@maastrichtuniversity.nl
Authors: Gijs H. Goossens and Ellen E. Blaak
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
Published December 10, 2020
Oxygen availability in key metabolic organs such as adipose tissue (AT) may contribute to the pathophysiology of obesity-related cardiometabolic complications (1). We have read with great interest the paper by Cifarelli and colleagues (2) in this issue of JCI, demonstrating that AT pO2 progressively declined from the metabolically healthy lean (MHL) to the metabolically healthy obese (MHO) to the metabolically unhealthy obese (MUO) participants, and was positively associated with insulin sensitivity.
These results are in agreement with rodent studies that have implicated AT hypoxia in obesity-related insulin resistance (1). As already indicated by the authors, studies in humans have yielded conflicting findings on AT oxygen partial pressure (pO2) in obesity. The observations by Cifarelli and colleagues (2) are in contrast with recent findings from our lab, showing that AT pO2 was higher in obese insulin resistant compared to age-matched lean as well as obese insulin sensitive men, and was inversely associated with insulin sensitivity (3, 4). In line, we also demonstrated that diet-induced weight loss decreased AT pO2 in humans, which was accompanied by improved insulin sensitivity (5). Notably, Cifarelli and colleagues (2) cite several studies that substantiate their findings. Yet, there are also reports demonstrating beneficial effects of hypoxia exposure on adipocyte insulin sensitivity (6) as well as whole-body insulin sensitivity and glucose homeostasis (7-9), which are not mentioned in their article and would rather support our recent findings (3-5).
It is increasingly evident that metabolic phenotypes may be distinct and that one size does not fit all. First, mainly women were included in the study by Cifarelli et al. (2), with somewhat unequal sex distribution across groups (more men in the MUO group)(2). Sex differences in AT biology (10), together with differences in body fat distribution between the MHO and MUO, might have confounded the results. Secondly, the study participants were relatively young (mean age 37.9±1.2 yrs) compared to the participants in our studies (3-5). The very high BMI and body fat percentage of the MUO at relative young age may represent a different obesity phenotype, and might imply that rapid fat mass expansion has occurred in these individuals. Thus, angiogenesis may have been insufficient to maintain normoxia in the rapidly expanding AT. The fact that adipocyte size was not different between the MHO and MUO groups, despite the higher degree of insulin resistance in the MUO (2), suggests a MUO phenotype that may be distinct from that representing a decline in AT mitochondrial function with increasing age and obesity, as frequently reported (1, 11). The MUO individuals in the study of Cifarelli et al. (2) may thus be characterized by rather normal AT mitochondrial function and oxygen consumption rates.
Lastly, since associations found in cross-sectional studies do not allow conclusions about causality, it will be interesting and important to perform mechanistic experiments in differentiated primary human adipocytes from lean and obese donors cultured under different oxygen levels, mimicking the human AT microenvironment, to further explore the mechanisms proposed in the paper by Cifarelli and coworkers (2).
Certainly, our previous work (3-5), together with the exciting novel findings by Cifarelli and colleagues (2) warrant further exploration of AT oxygenation in different (metabolic) phenotypes, taking differences in age, sex, ethnicity, diet and comorbidities into account. This knowledge will contribute to the development of novel treatment avenues to prevent and treat obesity-related cardiometabolic complications.
1. Lempesis IG, van Meijel RLJ, Manolopoulos KN, Goossens GH. Oxygenation of adipose tissue: A human perspective. Acta Physiol (Oxf). 2020;228:e13298.
2. Cifarelli V, Beeman SC, Smith GI, Yoshino J, Morozov D, Beals JW, et al. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J Clin Invest. 2020;130:6688-6699.
3. Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP, Konings E, et al. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation. 2011;124:67-76.
4. Goossens GH, Vogel MAA, Vink RG, Mariman EC, van Baak MA, Blaak EE. Adipose tissue oxygenation is associated with insulin sensitivity independently of adiposity in obese men and women. Diabetes Obes Metab. 2018;20:2286-2290.
5. Vink RG, Roumans NJ, Cajlakovic M, Cleutjens JPM, Boekschoten MV, Fazelzadeh P, et al. Diet-induced weight loss decreases adipose tissue oxygen tension with parallel changes in adipose tissue phenotype and insulin sensitivity in overweight humans. Int J Obes (Lond). 2017;41:722-728.
6. Lu H, Gao Z, Zhao Z, Weng J, Ye J. Transient hypoxia reprograms differentiating adipocytes for enhanced insulin sensitivity and triglyceride accumulation. Int J Obes (Lond). 2016;40:121-128.
7. Lecoultre V, Peterson CM, Covington JD, Ebenezer PJ, Frost EA, Schwarz JM, et al. Ten nights of moderate hypoxia improves insulin sensitivity in obese humans. Diabetes Care. 2013;36:e197-198.
8. Marlatt KL, Greenway FL, Kyle Schwab J, Ravussin E. Two weeks of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Int J Obes (Lond). 2020;44:744-747.
9. Serebrovska TV, Portnychenko AG, Drevytska TI, Portnichenko VI, Xi L, Egorov E, et al. Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression. Exp Biol Med (Maywood). 2017;242:1542-1552.
10. Goossens GH, Jocken JWE, Blaak EE. Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver. Nat Rev Endocrinol. 2020. DOI: 10.1038/s41574-020-00431-8 [Epub ahead of print].
11. Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends in endocrinology and metabolism: TEM. 2012;23:435-443.