Numao et al. Journal of Physiological Anthropology
https://doi.org/10.1186/s40101-021-00255-z(2021) 40:5

METHODOLOGY ARTICLE

Open Access

Differences in circulating fatty acid-binding
protein 4 concentration in the venous andcapillary blood immediately after acuteexercise
Shigeharu Numao* , Ryota Uchida, Takashi Kurosaki and Masaki Nakagaichi

Abstract
Background: Circulating fatty acid-binding protein 4 (FABP4) is a marker for various diseases. It would be highly
useful to have simple and less invasive techniques for the assessment of FABP4 concentrations in the clinicalresearch setting. The purpose of the present study was to assess the concordance of circulating FABP4
concentrations in venous and capillary blood both at rest and immediately after acute exercise in healthy young
males.
Results: Thirty-eight healthy young male adults aged from 19 to 25 years (mean age, 20.8 ± 1.2 years) wererecruited. Paired blood samples were taken from the cubital vein (venous) and fingertip (capillary) blood at rest
(resting state) and immediately after incremental exercise (exercising state). Blood samples were analyzed todetermine the circulating FABP4 concentration using an enzyme-linked immunosorbent assay. Pearson’s correlation
coefficients for circulating FABP4 concentrations between venous and capillary blood samples indicated a strong
positive correlation in both the resting and exercising state (resting state: r = 0.982, exercising state: r = 0.989, bothp < 0.001). The mean FABP4 concentration was similar between venous and capillary blood in the resting state (p =0.178), whereas it was significantly higher in capillary blood than in venous blood in the exercising state (p < 0.001).
Furthermore, Bland–Altman plots showed a non-significant bias (− 0.07 ± 0.61 ng/mL, p = 0.453) in the resting state,
whereas a significant bias (− 0.45 ± 0.61 ng/mL, p < 0.001) was observed in the exercising state.
Conclusions: These results indicate that capillary blood sampling can slightly overestimate circulating FABP4
concentrations under a physiologically dynamic state. However, the association between the venous and capillary
blood in terms of FABP4 concentration was very strong, suggesting that capillary blood sampling can detectchanges in FABP4 concentration in both physiologically steady and dynamic states.
Keywords: Acute exercise, Bland–Altman plot, Blood parameter, Adipokine* Correspondence: numashige@nifs-k.ac.jp
Department of Sports and Life Sciences, National Institute of Fitness andSports in Kanoya, 1 Shiromizu, Kanoya, Kagoshima 891-2393, Japan© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Numao et al. Journal of Physiological Anthropology(2021) 40:5

Introduction
Fatty acid-binding protein 4 (FABP4), also known as adipocyte FABP or adipose protein 2, is one of the fatty
acid-binding proteins. The FABPs are abundantly
expressed 14–15 kDa cytosolic lipid chaperones that
regulate lipid trafficking and responses in cells [1].
FABP4 is highly expressed in adipocytes and macrophages [2–4] and is primarily secreted from adipocytes
into the blood [5, 6].
Circulating FABP4 concentration is known as a biomarker for several disorders; increased circulating
FABP4 concentrations are associated with the increased
risk of various diseases, such as atherosclerosis [7, 8], insulin resistance [9], type 2 diabetes [10], hypertension [9,11], dyslipidemia [9, 12], cardiovascular diseases [13, 14],and cancer [15]. Notably, it has been also recently reported to be a potential biomarker for autism spectrum
disorder in children [16]. Thus, circulating FABP4 concentration is increasingly useful as a biomarker of disorders. Therefore, to broaden the use of circulating FABP4
as a biomarker in clinical research settings, simpler andless invasive techniques are required to determine its
concentrations.
To date, venous blood sampling is the most widelyused method for assessing circulating FABP4 concentrations. However, venous blood sampling is relatively invasive, requires a trained phlebotomist, generates
biological waste, creates participant discomfort, and interrupts physical activity (exercise) [17, 18]. Therefore,
capillary blood sampling from the fingertip has beenused as a simple alternative method to obtain blood
samples. Capillary blood sampling is minimally invasive,can be performed by non-specialist staff, helps avoid excessively restricting physical activities, and reduces thediscomfort of participants. Therefore, it is an efficientand convenient method for assessing circulating FABP4
concentration in clinical research settings.
In our previous study, we compared circulating FABP4
concentrations between venous and capillary blood [19];the concentrations were almost identical between venous
and capillary blood under a physiologically steady state(resting state). However, we did not investigate the concentrations under a physiologically dynamic state, such as
during exercise. A recent study reported the probability
that circulating FABP4 concentrations serve as a biomarker for estimating catecholamines response and lipolysis by adrenergic stimulation in vivo [20] as well as
for predicting a risk of various disorders. This suggests that the circulating FABP4 concentration will beapplied as a biomarker under a physiologically dynamic state when adrenergic stimulation enhanced.
This necessitates the analyses of circulating FABP4
concentration under various states to expand its application as a biomarker in clinical research setting.

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Besides, whether circulating FABP4 concentrations are
identical between venous and capillary blood under aphysiologically dynamic state is unclear. Thus, to establish capillary blood sampling as a viable alternative
for blood sampling in clinical research, it is necessary
to estimate the difference in circulating FABP4 concentrations between venous and capillary blood, evenunder a physiologically dynamic state.
The purpose of the present study was to assess theconcordance of circulating FABP4 concentrations between venous and capillary blood under both a physiologically steady (i.e., resting state) and dynamic state (i.e.,
immediately after exercise [exercising state]) in healthy
young males. We hypothesized that circulating FABP4
concentrations in the capillary blood would accurately
and precisely reflect those in venous blood under both
physiological states.

Materials and methods
Participants

Thirty-eight healthy young males (mean age, 20.8 ± 1.2
years) participated in the present study (Table 1). All
participants were undergraduate and graduate students
who responded to our advertisement featuring the experiment (experimental protocol, period, and measurement parameters) and reward details. The exclusion
criteria were as follows: applications 1) who were currently unhealthy (i.e., currently receiving medical treatments); 2) who had a history of metabolic disorders,cardiovascular diseases, or cancer in the past; and 3)
who were smoking or currently taking some medications
or supplements. This information was confirmed via
interview. The purpose, design, and risks involved in thepresent study were explained to all participants, andeach provided written informed consent. The study conformed to the principles outlined in the Declaration of
Helsinki and was approved by the Ethics Committee of
the National Institute of Fitness and Sports in Kanoya(approval number: 11-94).

Table 1 Physical characteristics of all participants (n = 38)
Mean±

Standard deviation

Age (years)

20.8

±

1.2

Height (cm)

172.8

±

6.3

Weight (kg)

72.4

±

12.0

Body mass index (kg/m2)

24.2

±

3.6

%fat (%)

17.3

±

6.2

Fat mass (kg)

12.9

±

6.5

Fat-free mass (kg)

59.5

±

8.0

Skeletal muscle mass (kg)

56.6

±

7.7

Numao et al. Journal of Physiological Anthropology(2021) 40:5

Study procedure

Participants completed all study components and measurements during a single session in the following order:(1) general health interview (current and previous medical history), (2) anthropometry and body composition
measurements, (3) venous and capillary blood samplingat rest, (4) acute incremental exercise, and (5) venous
and capillary blood sampling immediately after acute exercise. Participants were instructed to refrain fromstrenuous exercise for at least 24 h and from the consumption of meals except for water for at least 12 h before the study visit.
Anthropometry and body composition measures

For each participant, the height was measured to thenearest 0.1 cm using a stadiometer. Weight, body-fat
percentage (%fat), fat-mass (FM), fat-free mass (FFM),
and skeletal muscle mass (SMM) were measured to thenearest 0.1 kg using the dual-frequency impedance
method (RD-800; Tanita Corporation, Tokyo, Japan).
Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared.
Exercise procedure

After blood sampling at rest, an exercise test was performed on a cycle ergometer (Aerobike 75XLIII, Konami
Sports Life, Kanagawa, Japan). The exercise protocol,
after a brief individual warm-up period, consisted of a
30-watt increase every 2 min at 60 watts until 6 min andthereafter a 30-watt increase every 1 min until
exhaustion.
Blood sampling and analysis

Paired blood samples were collected from the cubital
vein and the fingertip at rest and after acute exercise.
Blood samples were collected in the following order:
venous blood and then capillary blood. The interval between the venous and capillary blood sampling was lessthan 3 min. Venous and capillary blood samplings were
performed using a single-use blood-collecting holder
with the needle and a single-use lancing device, respectively. Venous blood samples were collected in a 9-mL
tube containing a blood coagulation accelerator (Venoject ΙΙ, Terumo Corporation, Tokyo, Japan). Capillary
blood samples were collected in two 150-μL microtubes(‘Kantan’ tube, Eiken Chemical Corporation, Tokyo,
Japan). Approximately, 300 μL of the capillary blood wascollected in the microtubes within approximately 2 min.
Venous blood samples were centrifuged at 3000g for 10
min at 25 °C 30 min after collection; capillary blood samples were centrifuged at 2000g for 5 min at room
temperature 30 min after collection. Following centrifugation, the serum obtained from each sample wasPage 3 of 8transferred to plastic tubes and immediately stored at −80 °C until further analysis.
Circulating FABP4 concentrations were analyzed using
an enzyme-linked immunosorbent assay (ELISA) (R&D
system Inc., Minneapolis, USA; intra-assay coefficient ofvariation: < 5.8%). The ELISA procedure was performed
according to the manufacturer’s instructions. Eachsample was analyzed in duplicate. Samples from eachparticipant were analyzed in the same run to eliminate
inter-assay variation.
Statistical analysis

The data from four (resting state data) and five (exercising state data) participants were excluded from statisticalanalysis, because their blood samples were hemolyzed.
All data are presented as the mean ± standard deviation
and were tested for normality using the Kolmogorov–
Smirnov test. As normality was not assumed, FABP4
concentrations were log-transformed to estimate the difference and perform correlation analyses. The sample
size was calculated to detect a large effect (Cohen’s d =0.80 and r = 0.50). A sample size of 15–26 participants
would be required to have approximately 80% power todetect a large effect with 0.05 significance. A two-tailed
paired t test was used to compare the differences between the venous and capillary blood in circulating
FABP4 concentration in each resting and exercisingstate. Bland–Altman plots with 95% limits of agreement(± 1.96 × SD) [21] and Pearson’s correlation coefficientswere used to assess the correlation between the venous
and capillary blood samples in each resting and exercising state. A regression analysis was performed—with thedifference in circulating FABP4 concentrations between
the venous and capillary blood samples as the dependent
variable and the mean venous and capillary FABP4
concentrations as the independent variable—to evaluate
proportional bias in the Bland–Altman plots. The effectsize (ES) was calculated using Cohen’s d for thecomparison of circulating FABP4 concentration in the venous and capillary blood. The reference values for the ES
were as follows: Cohen’s d, small: ≥ 0.20, medium: ≥ 0.50,
or large: ≥ 0.80, and r, small: ≥ 0.10, medium: ≥ 0.30, or
large: ≥ 0.50. Statistical analyses were performed using the
SPSS Statistics version 24 (IBM Corporation, NY, USA).
Statistical significance was set at p < 0.05.

Results
Resting state

The data from 34 participants were included in the final
analyses. The log circulating FABP4 concentration did
not significantly differ between the venous and capillary
blood (venous: 1.68 ± 0.62 ng/ml, capillary: 1.70 ± 0.59
ng/ml, t = −1.376, degree of freedom (df) = 33, p =0.178, 95% confidence interval (CI): −0.068–0.013, ES:

Numao et al. Journal of Physiological Anthropology(2021) 40:5

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Fig. 1 Difference in circulating FABP4 concentration between the venous and capillary blood in the resting (a) and exercising state (b). Data arepresented as the mean ± standard deviation. There was no significant difference in circulating FABP4 concentration between the venous andcapillary blood in the resting state (p = 0.178). A significant difference in circulating FABP4 concentration between the venous and capillary blood
was observed in the exercising state (p < 0.001)

0.03) (Fig. 1a). The Pearson’s correlation coefficient forlog circulating FABP4 concentrations between the venous and capillary blood was significantly large (r = 0.982,
p < 0.001) (Fig. 2a). The Bland–Altman plots showed anon-significant bias (−0.08 ± 0.61 ng/mL, p = 0.453,
95%CI: −0.292–0.133) in circulating FABP4 concentrations between venous and capillary blood (Fig. 3a). The
regression analysis showed that the estimated regression
equation was not significant (y = 0.043x–0.356, p =0.111, estimated standard error (SEE) = 0.594, 95%CI:−0.010–0.096). The 95% limits of agreement ranged
from − 1.28 to 1.12 ng/mL. Two outliers were observedin the Bland–Altman plot, but 94.1% of plots were included in the 95% limits of agreement.

Exercising state

The data from 33 participants were included in the final
analyses. In contrast to the resting state, the log circulating FABP4 concentration in the capillary blood was significantly higher than that in the venous blood (venous:
1.89 ± 0.64 ng/ml, capillary: 1.97 ± 0.61 ng/ml, t =-3.953, df = 32, p < 0.001, 95%CI: −0.120 – −0.033) (Fig.
1b). However, the ES value was small (0.11). The Pearson’s correlation coefficient for log circulating FABP4
concentrations between venous and capillary blood
was significantly large (r = 0.989, p < 0.001) (Fig. 2b).
The Bland–Altman plots indicated a significant bias(−0.45 ± 0.61 ng/mL, p < 0.001, 95%CI: −0.666 –−0.230) in circulating FABP4 concentrations between

Fig. 2 Scatter plots of circulating FABP4 concentrations between the venous and capillary blood in the resting (a) and exercising state (b). Dark
line indicates an identical line. Pearson’s correlation coefficients, the resting state: r = 0.982 (p < 0.001), and the exercising state: r = 0.989(p < 0.001)

Numao et al. Journal of Physiological Anthropology(2021) 40:5

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Fig. 3 Bland–Altman plots showing the difference against the average circulating FABP4 concentrations between the venous and capillary bloodin the resting (a) and exercising state (b). Solid lines represent the mean bias and the 95% limits of agreement. There was no significant bias incirculating FABP4 concentrations between the venous and capillary blood in the resting state (p = 0.453). A significant bias in circulating FABP4
concentrations between the venous and capillary blood was observed in the exercising state (p < 0.001). There was no correlation between the
difference and average circulating FABP4 concentrations between the venous and capillary blood in both resting (p = 0.111) and exercising state(p = 0.170)

venous and capillary blood (Fig. 3b). The regression
analysis showed that the estimated regression equation was not significant (y = −0.031x–0.193, p =0.170, SEE = 0.60, 95%CI: −0.076–0.014). The 95%
limits of agreement ranged from − 1.65 to 0.75 ng/mL.
Two outliers were observed in the Bland–Altman
plots; however, 93.9% of plots were included in the
95% limits of agreement.

Discussion
The present study compared the circulating FABP4 concentration between the venous and capillary blood ineach resting and exercising states in young healthy
males. We hypothesized that circulating FABP4 concentrations in capillary blood would accurately and preciselyreflect those in the venous blood under both the physiologically states. However, our results only partiallyNumao et al. Journal of Physiological Anthropology(2021) 40:5

supported our hypothesis. We observed a strong correlation between the venous and capillary blood in the resting and exercising states. While circulating FABP4
concentrations were similar between the venous and capillary blood in the resting state, the FABP4 concentrations were significantly higher in the capillary bloodthan in the venous blood in the exercising state. Additionally, despite a non-significant bias of FABP4 concentrations in the resting state, a significant bias wasfound in the exercising state. These findings indicatethat capillary blood sampling can slightly overestimate
the circulating FABP4 concentration in the exercisingstate. However, there was a very strong association between FABP4 concentrations in the venous and capillary
blood, suggesting that capillary blood sampling can detect changes in FABP4 concentration in both resting andexercising states.
Our findings in the resting state support our previously reported results [19]. However, the characteristics
of participants in the present study slightly differed fromthat of our previous study [19]. In short, the BMI, FM,%fat, FFM, SMM, and circulating FABP4 concentrationin resting state were higher in the present study compared to our previous study [19]. Circulating FABP4
concentration is known to be correlated with BMI, FM,
and %fat [9, 19, 22]; this has been confirmed in thepresent study (Table S1). Meanwhile, circulating FABP4
concentrations were not significantly correlated with
FFM and SMM (Table S1), suggesting that the influenceof FFM and SMM on circulating FABP4 concentrationis small. Because %fat or FM was higher in the present
study, FABP4 concentrations measured in the restingstate (a non-log-transformed FABP4 concentration, venous: 6.4 ± 4.0 ng/ml, capillary: 6.5 ± 3.9 ng/ml) was
higher in the present study compared to that in our previous study (venous: 4.3 ± 2.4 ng/ml, capillary: 4.5 ± 2.5
ng/ml) [19]. Nevertheless, we found no differences in
FABP4 concentrations between the venous and capillary
blood in the resting state, and the corresponding Bland–
Altman plots indicated a non-significant negative andproportional bias. Additionally, the ES of the differencein the present study (ES = 0.03) was almost identical tothat in our previous study (ES = 0.04). Although therange of the 95% limits of agreement is narrower in thepresent study, the data included in the 95% limits ofagreement are similar to our previous study [19]. Taken
together, these findings suggest that capillary blood sampling is a reliable alternative to venous blood sampling
to assess circulating FABP4 concentrations under aphysiologically steady state, even in healthy young maleswith relatively higher BMI and fat mass.
Capillary blood sampling is commonly used to measure blood metabolite concentrations (e.g., glucose, lipoprotein, and lactate concentration) in clinical settings

Page 6 of 8

[23–27]. Because the capillary blood is an intermediate
between the arterial and venous blood, the metabolite
concentrations in the capillary blood tend to be higher
than that in venous blood [23–27]. In addition, this difference in metabolite concentrations between the capillary and venous blood is more marked in a state ofincreased blood metabolite concentrations (i.e., the postprandial and the exercising state) [23, 27–33]. This has
also been observed in cytokine concentrations [34]. Circulating interleukin-6 concentration is higher in capillary
than venous blood at rest, and the difference is greater
after acute high-intensity exercise [34]. In the present
study, the FABP4 concentration was elevated in the exercising state in both the capillary and venous bloodcompared with the resting state. This suggests that thesecretion of FABP4 into the circulation is accelerated
during exercise. Similar to the demonstrated differencein blood metabolite concentrations between the capillary
and venous blood under a physiologically dynamic state[23, 27–34], the acute increase in FABP4 concentration
may lead to the difference and negative bias in FABP4
concentrations between the capillary and venous bloodin the exercising state. Thus, capillary blood sampling
may slightly overestimate FABP4 concentrations under aphysiologically dynamic state, compared with venous
blood sampling.
While the FABP4 concentration in the capillary blood
was higher than that in venous blood in the exercisingstate, the absolute difference in FABP4 concentration
between the capillary and venous blood was slight, andthe ES was small. Additionally, the correlation in FABP4
concentrations between the capillary and venous blood
was very strong. In the exercising state, Bland–Altman
plots showed a non-significant proportional bias. It also
indicated that 93.9% of the plot was included within the
95% limits of agreement. Although the bias and the 95%
limits of agreement must be interpreted from a clinicalperspective, few studies have reported the circulating
FABP4 concentration during exercise. Only one study
reported a change in circulating FABP4 concentrations after approximately 10-min constant-load aerobic exercise [20]. Circulating FABP4 concentrations
were observed to increase from approximately 11 to
19 ng/mL (~ 8 ng/mL difference) during the exercise.
This change in circulating FABP4 concentration during the exercise is far beyond the bias and the 95%
limits of agreement range (~ 2.4 ng/mL) of the present
study. This would suggest that, given that the changein FABP4 concentration during aerobic exercise isrelatively large, capillary blood sampling is an acceptable method for the assessment of changes in circulating FABP4 concentrations during acute aerobic
exercise. However, capillary blood sampling is probably not reliable enough to detect the small changes

Numao et al. Journal of Physiological Anthropology(2021) 40:5

in FABP4 concentrations, thus limiting its applicability in clinical research.
The present study has several limitations. First, theparticipants were young healthy males; therefore, ourfindings may not be applicable to females, obese individuals, and older adults with or without diseases, and cancer patients. Circulating FABP4 concentrations arehigher in females and patients with metabolic disorders,cardiovascular diseases, and cancer than in young
healthy males [7–15]. It is necessary to consider the correlation of circulating FABP4 concentrations between
the venous and capillary blood in a population withhigher baseline circulating FABP4 concentrations. Second, sampling of the venous and capillary blood was
performed under both physiologically steady and dynamic conditions. However, the dynamic state modelledin this study acutely increases FABP4 concentrations in
the blood. Therefore, our findings may not be applicableto dynamic states that acutely decrease FABP4 concentration in the blood, such as after food consumption [6].
Thus, further studies in other populations and situations
are warranted to ascertain the generalizability of ourresults.
In conclusion, the findings of the present study demonstrate that the capillary blood sampling is a viable alternative to venous blood sampling under a physiologicallysteady state. While capillary blood sampling, comparedwith venous blood sampling, slightly overestimates FABP4
concentrations under a physiologically dynamic state, themethod is suitable for tracking changes in circulating
FABP4 concentration in healthy young males.

Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s40101-021-00255-z.
Additional file 1.

Abbreviations
FABP4: Fatty acid-binding protein 4; FABPs: Fatty acid-binding proteins;%fat: Percentage of body fat; FM: Fat mass; FFM: Fat-free mass; SSM: Skeletal
muscle mass; BMI: Body mass index; SD: Standard deviation; ES: Effect size;
CI: Confidence interval; SEE: Estimated standard error
Acknowledgements
The authors thank all the participants.
Authors’ contributions
SN and MN conceived and designed the experiments. SN, RU, TK, and MN
performed the experiments. SN and MN analyzed and interpreted the data.
SN, RU, TK, and MN wrote the paper. The authors read and approved thefinal manuscript.
Funding
This research was supported by the Japan Society Promotion of Science
Grant-in-Aid for Scientific Research (C) Grant Number JP18K10838.

Page 7 of 8

Availability of data and materials
All data generated or analyzed during this study are included in thispublished article.
Ethics approval and consent to participate
We ensure that this work has been carried out in accordance with the Codeof Ethics of the World Medical Association (Declaration of Helsinki) for
experiments involving humans, and informed consent was obtained from allparticipants. The study protocol was approved by the Ethics Committee of
the National Institute of Fitness and Sports in Kanoya.
Consent for publication
This is not applicable as the study does not have individual person’s data.
Competing interests
The authors declare that they have no competing interests.
Received: 21 October 2020 Accepted: 31 January 2021

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