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. 2013 Nov 13;3(1):75–80. doi: 10.4161/adip.27114

Adipose tissue oxygenation

Effects on metabolic function

Leanne Hodson 1,*
PMCID: PMC3917939  PMID: 24575375

Abstract

With the increasing prevalence of obesity there is a concomitant increase in white adipose tissue dysfunction, with the tissue moving toward a proinflammatory phenotype. Adipose tissue hypoxia has been proposed as a key underlying mechanism triggering tissue dysfunction but data from human, in vivo studies, to support this hypothesis is limited. Human adipose tissue oxygenation has been investigated by direct assessment of tissue oxygen tension (pO2) or by expression of hypoxia-sensitive genes/protein in lean and obese subjects but findings are inconsistent. An obvious read-out of hypoxia is the effect on intermediary metabolism, and we have investigated the functional consequences, in terms of a “metabolic signature” of human adipose tissue hypoxia in vivo. Here, we discuss the different approaches used and the importance of integrative physiological techniques to try and elucidate what defines adipose tissue hypoxia in humans.

Keywords: human, hypoxia, adipose tissue, metabolism, oxygen tension, metabolic signatures

In recent years studies investigating subcutaneous white adipose tissue (WAT) metabolism, function, and physiology, in relation to health and disease have substantially increased. No longer is WAT seen as a metabolically inactive fuel storage site, rather it is a complex organ that plays integral roles in many metabolic processes; typically responding rapidly and dynamically to changes in nutritional state.1-3 In man, subcutaneous abdominal WAT is often the biggest single fat depot that has a large capacity for expansion when faced with excess nutrition.4,5 Expansion of adipose tissue does not necessarily translate to an increased risk of metabolic diseases, such as, type 2 diabetes, fatty liver disease, and cardiovascular disease (CVD); intriguingly a proportion of obese individuals appear to remain metabolically healthy despite having an excess of body fat.6 Thus, it appears impaired function, rather than amount of adipose tissue, plays an important role in the pathophysiology of metabolic disease risk.5,7,8 An expansion of WAT mass may result in an infiltration of macrophages leading to inflammatory responses via molecules such as TNF-α, IL-6, and MCP-1, all of which have been implicated in the development of pathological changes in adipose tissue physiology.5,9-11 The root cause of human obesity-related adipose tissue dysfunction is widely debated; a commonly held, but largely unsubstantiated, view is that oxygen deficiency or “hypoxia” within the tissue is the underlying cause, moving the tissue toward a proinflammatory environment.6,12-15

In 2004 Trayhurn and Wood15 first put forward the notion of obesity-related WAT hypoxia as the culprit for adipose tissue dysfunction. Since this time a number of studies have been undertaken, typically using in vitro cellular and animal models,14,16-21 with only a limited number of investigations in vivo in humans.22-24 Key to the concept of adipose tissue hypoxia is the supply of oxygen to the tissue, with blood flow playing an integral role in tissue oxygenation and function. Blood circulation carries oxygen around the body and as it passes through organs and tissues there is progressive oxygen consumption.25 At each step of tissue oxygen diffusion, there is a physiological decrease in the partial pressure of oxygen (pO2) until reaching 1 to 2 mmHg within the mitochondria of many tissues.26 In severe obesity, it has been well-recognized that arterial blood oxygenation is markedly compromised, with arterial oxygenation between 48 and 83 mmHg (compared with the expected value of approximately 100 mmHg for healthy adults).25,27-29

Tissue pO2 reflects the balance between oxygen delivery and consumption. A consistent observation across studies is that adipose tissue blood flow is markedly lower in obese than non-obese subjects in both the fasted2,22,23,30,31 and postprandial2,22 states. Therefore, it could be anticipated that oxygen delivery to the tissue is compromised in obese individuals. White adipose tissue changes in composition with obesity, with an enlargement of lipid droplets.32,33 However, it is only the non-lipid droplet part of the adipocyte that requires oxygen for metabolic processes, so the delivery of oxygen per unit tissue may not be very different. Furthermore, adipose tissue from obese compared with lean individuals has a downregulation in the expression of metabolic pathways, including mitochondrial oxidative pathways.2,34 As the expansion of fat tissue often leads to larger sized adipocytes;22,35 this could theoretically increase the diffusion distance for O2, and angiogenesis may play a critical role in providing expanding adipose tissue with adequate oxygen and nutrients.36 Trayhurn and Wood15 have proposed that the rate at which fat mass is accrued may be important, with angiogenesis being insufficient in situations where weight gain is very rapid and extensive, such as under experimental conditions that have investigated dietary-induced obese mice.14,19 A lower expression of angiogenic genes and capillarization has been found in the subcutaneous abdominal WAT of obese compared with lean individuals,22,24 suggesting angiogenesis may not be sufficient to maintain adequate oxygenation within the entire depot.37

Adipose tissue accounts for around 5% of whole-body O2 consumption in normal-weight individuals;38 thus it is not a large consumer of O2. Human experimental data on adipose tissue O2 consumption is sparse. We have recently examined adipose tissue O2 consumption, using arterio-venous difference methodology, with selective venous catheterization of subcutaneous abdominal WAT, in individuals (n = 52) across a range of adiposity (BMI 19.5–54.1 kg/m2) to determine gas exchange and substrate utilization in order test the hypothesis of adipose tissue hypoxia in obesity as a potential driver of dysfunction.23 All subjects recruited were considered metabolically healthy however three subjects had impaired fasting glucose (based on their plasma glucose being >6.1 mmol/L) but none were diabetic. In line with others39 there was no difference in fasting plasma nonesterified fatty acid (NEFA) concentrations with increasing obesity. We found a non-significant trend for decreasing O2 consumption with increasing obesity. In vitro work has reported O2 consumption per adipocyte to be higher, but O2 consumption per gram of tissue to be lower, in samples from obese compared with lean subjects.40

Adipocytes, like other cells in the body, require energy for a variety of metabolic activities. In vitro work undertaken in the 1940s and 60s41,42 has suggested that this energy is primarily obtained by glucose catabolism. By undertaking carefully controlled studies, with selective venous catheterization of subcutaneous abdominal WAT we have been able to corroborate the hypothesis in vivo that in the fasting state, WAT oxidizes predominantly glucose.23 With feeding, adipose tissue RQ markedly increased to be significantly greater than 1.0,23 indicative of net lipogenesis.43 It is now well recognized that human adipose tissue has the capacity for de novo lipogenesis (DNL),44-46 and by measuring the tissue-specific RQ in the fasted and fed state, we have been able to provide the first indication that the pathway becomes active after meals during normal energy balance.

Determining adipose tissue oxygenation is challenging, with direct measurements of adipose tissue pO2 being made in murine and human models (Table 1), using a variety of techniques. In animal models, the interstitial oxygenation of epididymal fat pads has been assessed by needle-type optic-fiber oxygen sensor.14,19 Ye et al.14 reported a 70% lower interstitial pO2 within epididymal fat pads of ob/ob compared with lean mice. The authors suggested this was indicative of adipose tissue hypoxia, rather than systemic hypoxia, as there was no notable difference in the pO2 of venous blood (inferior vena cava) between the groups.14 In humans, oxygen tension has been assessed in upper arm subcutaneous WAT by silastic tonometer in individuals undergoing surgery,47-49 and in subcutaneous abdominal WAT by a Clark-type electrode24 or continuous measurement based on microdialysis.22 The pO2 of human adipose tissue has been reported to be between 36 and 68 mmHg.22,24,47-49 The pO2 of upper arm subcutaneous WAT has been found to be significantly lower in the obese (BMI >40 kg/m2) compared with non-obese (BMI <30 kg/m2) adipose tissue by some,27,47,48 but not all;49 with no difference being noted between groups in arterial pO2.47-49 Pasarica et al.24 reported subcutaneous abdominal WAT pO2 to be significantly lower (approximately 11 mmHg) in overweight/obese compared with lean individuals. In contrast, Goossens et al.22 noted adipose tissue pO2 to be markedly higher (approximately 20 mmHg) in obese compared with lean individuals. Neither study reported arterial pO2, so it is unknown if systemic oxygenation differed between the groups.22,24 The discrepancy in findings may well be explained by the different methodologies used, which may not capture O2 available within the adipocyte and subjects studied, along with the fact that this work has assessed local, rather than whole depot oxygen tension; it is plausible that oxygen tension may be higher or lower within another region of the adipose tissue depot. The level of oxygen tension that defines oxygen deficiency or hypoxia within human adipose tissue remains to be elucidated.

Table 1. Summary of studies measuring adipose tissue oxygenation.

Author Species Site Method pO2 measure Phenotype AT pO2 (mmHg) PaO2 and AT pO2 (mmHg) measures
Fleischmann et al.47 H Subcut upper arma Silastic tonometer n = 15 (10 M, 5 F); Age: 43 y; BMI: 24 57 (15)b  
n = 20 (4 M, 16 F); Age: 40 y; BMI: 46 41 (10)b  
Kabon et al.48 H Subcut upper arma Silastic tonometer n = 23 (12 M, 11 F); Age: 44 y; BMI: 24 Right armc: 54 (47, 64)d PaO2 ~150 mmHge: 57 (53, 72)d
Left armc: 62 (49, 68)d PaO2 ~300e: 76 (56, 92)d
n = 23 (3 M, 20 F); Age: 44 y; BMI: 51 Right armc: 43 (37, 54)d PaO2 ~150 mmHge: 36 (30, 55)d
Left armc: 42 (36, 60)d PaO2 ~300 mmHge: 47 (39, 75)d
Hiltebrand et al.49 H Subcut upper arma Silastic tonometer n = 7 (2 M, 5 F); Age: 31 y; BMI: 22 52 (10)b 2 l/min O2 (via nasal prongs): 77 (25)b
6 l/min O2 (via face mask): 125 (43)b
PaO2 ~200 mmHge: 121 (25)b
PaO2 ~300 mmHge: 145 (41)b
n = 7 F; Age: 37 y; BMI: 46 58 (8)b 2 l/min O2 (via nasal prongs): 79 (24)b
6 l/min O2 (via face mask): 125 (43)b
PaO2 ~200 mmHge: 114 (23)b
PaO2 ~300 mmHge: 154 (33)b
Pasarica et al.24 H Subcut Abdom Polarographic micro clark-type electrode n = 9 (5 M, 4 F); Age: 23 y; BMI: 22 55.4 (9.1)b  
n = 12 (6 M, 6F); Age: 39 y; BMI: 32 46.8 (10.6)b  
Goossens et al.22 H Subcut Abdom Optochemical, continuous monitoring via microdialysis n = 10 M; Age: 56 y; BMI: 23 44.7 (5.8)f  
n = 10 M; Age: 60 y; BMI: 34 67.4 (3.7)f  
Ye et al.14 Mu Epid Needle-type fiber-optic oxygen sensor ob/ob (wt 53 g) and C57BL/6 (wt 33 g); Age: 12 wk ob/ob: 15.2g  
C57BL/6: 47.9g
Yin et al.19 Mu Epid Needle-type fiber-optic oxygen sensor ob/ob and C57BL/6; Age: 6 and 12 wk C57BL/6: 6 and 12 wk: 57–60g  
ob/ob: 6 wk: 34.8g; 12 wk: 20.1g
Zhang et al.63 Mu Epid Needle-type fiber-optic oxygen sensor C57Bl/6; Age: 6 and 23 mo 6 mo: ~30g  
23 mo: ~21.7g
Inguinal 6 mo: ~35g  
23 mo: ~38g
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Abbreviations: H, human; Mu, murine; M, male; F, female; y, years; BMI, body mass index (kg/m2); Subcut, subcutaneous white adipose tissue; Abdom, abdominal; Epid, Epididymal; wt, weight; mth, month; wk, week; AT, adipose tissue; pO2, partial pressure of oxygen (mmHg), PaO2, partial pressure of arterial oxygen (mmHg). aSubjects were patients undergoing elective surgery; bmean (SD); cmeasurement made the morning after surgery; dmedian (25th, 75th percentile); eoxygen given to achieve specific arterial oxygen pressure; fmean (SEM); gdata estimated from figure and some reported in text.

The studies described above have focused on WAT; however, with recent evidence confirming active brown adipose tissue (BAT) in adults; investigations into the metabolic responses of this depot have been undertaken.50-53 BAT is highly vascularized and a consistent finding has been that blood flow in “unstimulated” BAT is higher than that in WAT per unit mass.50-52 When cold-stimulated, blood flow significantly increases in BAT, while there is no change in WAT.50-52 Blood flow in “stimulated” BAT is significantly higher in lean (BMI = 22.7 kg/m2) compared with obese (BMI = 34.0 kg/m2) subjects, despite “unstimulated” blood flow being remarkably similar.53 Notably, lean subjects have a significantly higher mass of BAT compared with obese subjects (24 ± 24 g vs 14 ± 29 g, [mean ± SD], respectively).53 The pO2 of BAT in unknown but it could be anticipated, that due to the higher blood flow the pO2 would be higher than WAT. Blood flow in beige/brite adipose tissue has not yet been reported.

In vitro cellular studies have tended to use a pO2 of 7.6 mmHg (or 1% O2) as a model of hypoxia;12-14,16,17 which is considerably lower than the reported pO2 (36–68 mmHg) of human adipose tissue (Table 1). A consistent finding from in vitro experiments, where cells have been exposed acutely to 1% O2, is robust changes in molecular markers of hypoxia, such as hypoxia-inducible factor-1α (HIF-1α), the key operator and central controller of oxygen-related gene expression.15,20,21 Notably, HIF-1α expression is very responsive to the local environment as it is rapidly degraded, within minutes, on return to normoxia, (21% O2, 160 mmHg).25 Of the three studies that have assessed human subcutaneous abdominal WAT from lean and obese subjects for the genetic hallmarks of hypoxia two studies found the expression of HIF-1α or HIF-1α target gene expression was not consistently reflected in obese adipose tissue.22,24 Cancello and colleagues54 reported HIF-1α expression to be significantly higher in the subcutaneous WAT from morbidly obese (BMI 48 kg/m2) compared with lean (BMI 22 kg/m2) subjects. Drastic weight-loss over a 3 mo period in the morbidly obese subjects resulted in subcutaneous WAT HIF-1α expression decreasing to be comparable to the control group.54 Animal work has suggested HIF-1 subunits are linked to adipocyte biology and an overexpression of HIF-1α in adipose tissue decreases glucose tolerance, increased liver fat and adipose tissue fibrosis.55 In contrast, adipose tissue-selective inactivation of HIF-1 subunits has been reported to cause striking changes in both adipose tissue functions and systemic insulin sensitivity, as recently reviewed in reference 18.

The quantification of human adipose tissue pO2 is not trivial and the reported differences in tissue pO2 are difficult to interpret due to the complexity of the measurement. As discussed above, there are a number of determinants of tissue oxygenation along with the position of the measurement “probe”, knowing if all available O2 with the adipocyte is captured, O2 solubility, local temperature, hematocrit, heterogeneity of tissue gas tension, and limitations of tissue sensors, as reviewed.56 Thus, alternative approaches, which do not rely on the complexities of quantifying pO2, but still depend on pO2, need to be taken to determine adipose tissue oxygenation; the obvious readout of hypoxia is the effect on function, which can be assessed by the measurement of metabolic substrate utilization by the tissue. Assessing the metabolic function of WAT subcutaneous adipose tissue can be achieved using arterio-venous difference methodology.57,58 The anterior abdominal wall has a reasonably well-defined pattern of venous drainage and is, in most people, a large depot.57 If large areas of the tissue are “hypoxic” this will markedly alter function, which will be reflected in the venous blood draining adipose tissue, whereas small, localized areas of tissue hypoxia may not be reflected by the arterio-venous approach.

We have addressed the question of obesity-related adipose tissue hypoxia by assessing functional consequences that is seeking a metabolic signature of adipose tissue hypoxia as a potential driver of adipose tissue dysfunction in obesity.23 Although cellular models have not used concentrations of oxygen that best reflect the physiology of human adipose tissue, these models provide insight into potential metabolic signatures. An initial cellular response to a low oxygen environment is a reduction in oxidative phosphorylation which results in the cell switching to anaerobic glycolysis for its energy production, thus there is an increased demand for glucose.13 A consequence of this shift is an increase in lactate production, which has to be rapidly exported from the cell.13 Exposure of the human preadipocyte cell line (SGBS) to 1% O2 for 24 h resulted in a 2-fold increase in lactate in the medium compared with cells incubated under normoxia (21% O2).17 The potential fates for glucose taken up into adipose tissue are conversion to lactate, conversion to glycerol-3-phosphate which is utilized for fatty acid reesterification, or it can be partitioned between oxidation or storage as glycogen and possibly lipid.57 Lactate is released by human adipose tissue in vivo in the fasting1,57,59,60 and postprandial states.1,59,61 We hypothesized that in obese adipose tissue, with low oxygenation, there would be repartitioning of glucose toward lactate production, rather than glycerol-3-phosphate production, oxidation or storage. If there were an increase in glycolysis, then the production of pyruvate, the immediate precursor of lactate, would be increased. Thus, if cellular hypoxia were present in adipose tissue there would be a change in the cytosolic redox state; that is the NADH/NAD+ ratio would be increased driving the equilibrium from pyruvate toward lactate, accelerating lactate production.62 A possible consequence of glucose repartitioning could be less fatty acid reesterification within the tissue which may lead to an increased fatty acid release. We found no evidence of an increase in glucose uptake across adipose tissue with increasing obesity, nor did we find any evidence for a lack of provision of glycerol-3-phosphate, suggesting that glucose partitioning toward this pathway is not impaired with increasing obesity.23 We also found no evidence that glucose was repartitioned toward lactate and pyruvate production, as the proportion of glucose uptake released as lactate and pyruvate was not increased in obesity and the tissue-specific change in lactate to pyruvate ratio was unrelated to BMI.23 Taken together, in the absence of metabolic signatures typical for hypoxia, our observations argue against the presence of a low oxygen tension in adipose tissue in obesity; however our data do not allow comment on fat mass expansion and associated macrophage infiltration or inflammation. Nevertheless, work is still required to define the normal range of pO2 in obese and non-obese adipose tissue and the cellular responses in human adipose tissue for a given pO226 as 1% O2, as used in cellular models, does not reflect human physiology.

There is a lot of discussion on the cause of human adipose tissue dysfunction with adipose tissue hypoxia or oxygen deficiency, often being suggested as the root cause of driving the tissue toward a proinflammatory phenotype despite limited evidence from human studies. Studies need to be undertaken to determine the level of pO2 that defines adipose tissue oxygen deficiency (i.e., how low is too low) and how intermittent, acute, and chronic exposure to this pO2 affects adipose tissue function. To fully elucidate the role of adipose tissue pO2 on tissue function, investigations need to take an integrative approach, bringing together an understanding of how O2 delivery and consumption, metabolic signatures (e.g., biochemical parameters, inflammatory markers, and adipokines), and genetic hallmarks are related to adipose tissue function and the pathophysiology of metabolic disease risk in humans.

Disclosure of Potential Conflicts of Interest

The author has no conflicts of interest to declare.

Acknowledgments

The author thanks Professors Keith Frayn, Fredrik Karpe, and Mrs Sandy Humphreys for their helpful discussion and constructive comments. L Hodson is a British Heart Foundation Intermediate Fellow in Basic Science.

Hodson L, Humphreys SM, Karpe F, Frayn KN. Metabolic signatures of human adipose tissue hypoxia in obesity. Diabetes. 2013;62:1417–25. doi: 10.2337/db12-1032.

10.4161/adip.27114

Footnotes

References

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