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Improved Insulin Sensitivity and Irisin after a Dietary Weight-Lowering Program in Obese, Otherwise Healthy Subjects

Authors:
  • Biomedical Research center of the Slovak Academy of Sciences

Abstract and Figures

Recent studies suggest that serum irisin might be a predictor of insulin resistance in obese subjects. The aim of the study was to analyze the effect of life style intervention on insulin sensitivity, irisin, and visfatin concentrations. Methods: A group of 43 obese patients (13M/30F; 43.0 ±12.4 years; BMI 31.2 ± 6.3 kg/m2) participated in a weight loss interventional program (NCT02325804) following an 8-week program consisting of hypocaloric diet (-30% energy intake) and physical activity 150 minutes/week. Insulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices according Matsuda and Cederholm were calculated (ISIMat and ISICed). Plasma ALT, AST, irisin, visfatin, and physical fitness were measured. Results: The average reduction of body weight was 6.8±4.9 kg (0-15 kg; p=0.0006), accompanied with significant reduction of body fat mass (p=0.03), and waist circumference (p=0.02). Insulin sensitivity improved (IR HOMA 2.71±3.90 vs. 1.24 ±0.83; p=0.01; ISIMat 6.64±4.38 vs. 8.93±5.36 p ≤ 0.001; ISICed 59.1±21.4 vs. 64.7±22.2 p=0.03). Total and LDL cholesterol, as well as triglycerides decreased (p=0.02, p=0.02, p=0.resp.), Physical fitness significantly improved after intervention (as measured by VO2 max: 25.1±5.9 vs. 28.0±6.0 ml.kg-1.min-1, p ≤ 0.001). Plasma irisin significantly decreased after intervention (233 ± 66 vs. 167 ± 88 ng/mL; P ≤ 0.001), while visfatin levels did not changed. Conclusion: Eight weeks of diet and physical activity intervention program in obese otherwise healthy subjects leaded to improvement of insulin sensitivity, as well as physical fitness and lowering of plasma irirsin levels. Irisin strongly reflects body fat mass, suggesting that the irisin circulating levels are conditioned by adiposity level. Disclosure A. Penesova: None. Z. Radikova: None. B. Bajer: None. M. Vlcek: None.
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ENDOCRINE REGULATIONS, V. , N. , –, 
doi:10.2478/enr-2024-0013
Plasma irisin and the brain-derived neurotrophic factor levels in
sedentary subjects: eect of 8-weeks lifestyle intervention
Zoa R 1,2, Lucia M 1, Carmen E 2, Boris B1, Andrea H 1,
Richard I 1,3, Miroslav V 1,2, Adela P 1,4
1Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava,
Slovakia; 2Faculty of Medicine, Slovak Medical University in Bratislava, Bratislava, Slovakia; 3Institute of Physiology,
Faculty of Medicine, Comenius University, Bratislava, Slovakia; 4Department of Biological and Medical Science, Faculty
of Physical Education and Sport, Comenius University in Bratislava, Bratislava, Slovakia
E-mail: miroslav.vlcek@savba.sk
Objectives. Sedentary lifestyle increasingly observed in the population contributes to the in-
cremental incidence of obesity, cardiovascular diseases, mental disorders, type 2 diabetes, hyper-
tension, dyslipidemia, and others. Physical inactivity together with an imbalance in caloric intake
and expenditure leads to a loss of muscle mass, reduced insulin sensitivity, and accumulation of
the visceral fat. Organokines (adipokines, myokines, hepatokines, etc.) serve in the organism for
inter-organ communication. However, human studies focused on the exercise-related changes in
plasma levels of certain myokines have produced contradictory results. In the present study, we
veried a hypothesis that myokine irisin, which is expected to increase in response to physical
activity, induces brain-derived neurotrophic factor (BDNF) production and by this way mediates
the benecial eect of exercise on several brain functions.
Subjects and Methods. Women (n=27) and men (n=10) aged 44.5±12.0 years, who were sed-
entary and overweight/obese (men ≥25%, women ≥28% body fat), participated in the study. e
eect of an 8-week intensive lifestyle intervention (150 minutes of moderate physical activity
per week, diet modication, and reduction of caloric intake) on the selected organokines (irisin,
BDNF) in the context of an expected improvement in cardiometabolic status was examined.
Results. e 8-week lifestyle intervention resulted in a signicant (p<0.05) reduction in body
mass index, body fat, blood pressure, insulin resistance, lipid and liver parameters, and irisin levels
(p<0.001). However, BDNF increase in the whole group did not reach statistical signicance. Aer
the improvement of cardiometabolic parameters, a signicant decrease in irisin and increase in
BDNF levels were also observed in the subgroup with unsatisfactory (≤5%) body weight reduc-
tion. Neither relationship between irisin and BDNF levels, nor eect of age or sex on their levels
was observed.
Conclusions. We cannot conrm the hypothesis that exercise-induced irisin may increase the
BDNF levels, whereas, the organokine levels in the periphery may not completely reect the pro-
cesses in the brain compartments. e observed decrease in irisin levels aer 8-week intensive
lifestyle intervention program, which was in contrary to its supposed mechanisms of action and
dynamics, suggests the presence of several yet undiscovered impacts on the secretion of irisin.
Key words: irisin, BDNF, physical activity, sedentary lifestyle, cardiometabolic improvement
Corresponding author:
Miroslav Vlcek, MD, PhD, Institute of Clinical and Translational Research Biomedical Research Center,
Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia; phone: +421-2-3229 5244; e-mail: miroslav.vlcek@savba.sk.
116 Irisin and BDNF response to 8-weeks lifestyle intervention
e obesity and obesity related diseases are
considered a global world problem leading to serious
health problems. In 2016, about 1.9 billion adults
worldwide had body mass index (BMI) >25 kg/m2,
including 650 million adults with obesity. Addition-
ally, almost 400 million children and adolescents
are suering from overweight/obesity (WHO 2022).
Based on the recent data (from 2020), more than
2.6 billion people worldwide are obese/overweight
with an unfavorable expectation of 4 billion in 2035
(World Obesity Federation 2023).
e mechanisms how the obesity contributes to
the development of metabolic syndrome, its features,
and complications (insulin resistance, hyperten-
sion, diabetes mellitus type 2 (T2DM), dyslipidemia,
low-grade inammation, cardiovascular diseases,
nonalcoholic fatty liver disease, obstructive sleep
apnea, dierent types of cancer etc.) are extensively
studied (Fasshauer and Bluher 2015).
Physical inactivity and disbalance in the caloric
intake and expenditure (in favor of overnutrition) lead
to a visceral fat accumulation, obesity, loss of muscle
mass, impaired glucose tolerance, decreased insulin
sensitivity, and associated diseases (Dirks et al. 2016).
Overweight and obese individuals are repeatedly
recommended to follow two main health advices that
can reduce the risk of health problems: energy intake
decrease and physical active increase (Dinas et al.
2014). Disappointing weight loss is oen followed by
a poor compliance and loss of motivation. However,
the benecial eects of exercise (decreased systolic
and diastolic blood pressure, lower waist circumfer-
ence, improved cardiorespiratory tness, etc.) are
not dependent on the weight loss itself and can be
achieved even in the presence of lower-than-expected
exercise-induced weight loss (King et al. 2009).
e communication between the tissues and
organs in the body, such as adipose tissue, liver,
skeletal muscle, immune system, brain, gut, pancreas,
vessels, bones, etc., is a complex. e increasing
understanding that how the tissues communicate
by secretion of various substances, e.g., organokines
(adipokines, hepatokines, myokines, etc.) aecting
local and distant organs, has proposed the concept
of the inter-tissue crosstalk (Meex and Watt 2017).
Individual tissues produce relevant organokines. e
adipose tissue produces more than 600 adipokines
(Lehr et al. 2012), hepatocytes produce more than 500
hepatokines, and the skeletal muscle more than 600
myokines (Gorgens et al. 2015). In addition, many
substances are produced in dierent organs having
several sites of origin and many of them are still
unidentied.
In the resting state and during the contraction,
the skeletal muscle secretes many myokines, which
are supposed to mediate exercise-induced benecial
health eects. One of the myokine, which is secreted by
skeletal muscle, is irisin. Although initially described
as a myokine, irisin has multiple sites of origin, i.e.
besides skeletal and cardiac muscles, it is secreted
from the adipose tissue, pancreas, kidney, and liver
(Bostrom et al. 2012). Irisin induces browning of the
subcutaneous fat adipocytes (Bostrom et al. 2012),
weight loss with increased energy expenditure, and
loss of the visceral adipose tissue (Gonzalez-Gil and
Elizondo-Montemayor 2020). Moreover, irisin has
also anti-inammatory and antioxidative properties,
which by acting on the hepatocytes can decrease
the hepatic steatosis (Gonzalez-Gil and Elizondo-
Montemayor 2020). Irisin acts aer binding to a
recently discovered αV integrin receptor (Kim et al.
2018; Mu et al. 2023).
By demonstrating irisin’s benecial eects on
browning of the subcutaneous fat adipocytes,
improving energy homeostasis, and obesity in animal
and in vitro studies (Bostrom et al. 2012; Polyzos et al.
2018), it has been considered to be a promising target
for the therapy of obesity. However, human studies
have brought several contradictory results, either
supporting (Bostrom et al. 2012; Miyamoto-Mikami
et al. 2015) or refuting the hypothesis of an increased
circulating irisin in response to solitary or regular
exercise. e later nding has revealed no change
(Kurdiova et al. 2014) or even decreased levels (Qiu
et al. 2015) of this myokine aer chronic exercise
training.
Brain-derived neurotrophic factor (BDNF) is a
growth factor ubiquitously expressed in the brain
regions related to cognitive functions (Carlino et al.
2013). It is involved in the dierentiation of neurons,
formation and plasticity of synapses, and processing
associated with survival, reparation, and protection
of the central nervous system tissues (Benarroch
2015). Its expression is not limited to the nervous
system. Its function has been described in multiple
non-neural tissues, such as heart, lung, skeletal
muscle, adipose tissue, kidneys, vascular system, and
blood cells (Esvald et al. 2023).
Decreased BDNF levels are associated with
cognitive decits in elderly population (Shimada
et al. 2014) and involved in the pathophysiology
of many neurodegenerative disorders including
Alzheimer’s and Parkinson’s diseases, multiple
sclerosis, and Huntington’s disease (Wang et al. 2016;
Prokopova et al. 2017; Ng et al. 2019; Zhou et al. 2021)
as well as neuropsychiatric disorders, such as major
117R, et al.
depressive disorder (Porter and O’Connor 2022) or
schizophrenia (Yang et al. 2019). BDNF levels are also
associated with obesity playing an important role
in the regulation of energy balance, controlling the
appetite, and managing the body weight (Sandrini
et al. 2018). On the other hand, higher levels of this
neurotrophic factor have been observed aer physical
activity (Leung et al. 2023).
In the present study, we veried a hypothesis
that myokine irisin, which is expected to increase
in response to physical activity, induces BDNF
production and by this way mediates the benecial
eect of exercise on several brain functions. e
aim of the present study was to examine the eect
of 8-weeks intensive lifestyle changes (diet and 150
min of moderate physical activity per week) on the
organokine irisin levels in context with the expected
improvement of the cardiometabolic status. e
assumption that the weight loss itself is not a prereq-
uisite for improving the cardiometabolic parameters
and that the lifestyle changes alone may lead to a
signicant improvement in the observed parameters,
was also assessed. For this reason, a subgroup of
subjects who achieved lower-than-expected weight
loss (LWL subgroup) was transferred into the group
of volunteers and evaluated separately.
Subjects and Methods
Design of the study. A prospective longitudinal
study consisted of an 8-weeks weight loss interven-
tion program including a 30% reduction in intake
of weight-maintaining calories and recommended
moderate aerobic exercise of 150 min per week.
e study, registered on ClinicalTrials.gov under
NCT02325804, was performed at the Institute of
Clinical and Translational Research, Biomedical
Research Center of the Slovak Academy of Sciences,
Bratislava, Slovakia. e project was approved by
the Ethic committee of the Bratislava self-governing
region (No: 05239/2016/HF). e study was performed
in accordance with the Declaration of Helsinki
principles. Aer a comprehensive explanation of the
particular tests and detailed instructions concerning
the diet and exercise program, the signed informed
consent was obtained from all participants before
being enrolled in the program.
Participants. e participants of our program,
aged 20–69 years were all Caucasian volunteers
(men n=10, women n=27) with central obesity,
expressed as higher amount of body fat (men ≥25%,
women ≥28%) and sedentary lifestyle, assessed using
the Slovak version of the Lagerros questionnaire
(Lagerros et al. 2006), which is a useful method
to estimate the average daily energy expenditure.
From the participants who completed the program,
available plasma and serum samples of 37 subjects
fullling the inclusion (age, obesity, and sedentary
lifestyle as mentioned above) and exclusion criteria
were examined. e exclusion criteria were: current
symptoms or treatment of chronic diseases (diabetes
mellitus on insulin therapy, any serious endocrine,
rheumatic, metabolic, hematologic, pulmonary, liver,
cardiovascular disease), malignancies, recent trauma
or surgery interfering with the intervention program,
pregnancy and breastfeeding, tobacco, alcohol or
drug addiction.
Study protocol. e participants were examined
twice aer enrolment in the study and aer
completing the intervention program. e volunteers
were asked to fast 12 h prior to the study and avoid
making intensive physical exercise 24 h before the
examination. e tests were performed at 08:00 a.m.
in the outpatient clinic of the internal medicine and
diabetes at the Institute of Clinical and Translational
Research, Biomedical Research Center of the Slovak
Academy of Sciences, Bratislava, Slovakia.
In all participants, anthropometric measurements
(height, weight, waist, and hip circumference) were
performed. e percentage of total body fat was
examined by bioimpedance method (InBody R20,
InBody Co., Ltd., Seoul, South Korea). Blood pressure
was measured aer at least 5 min rest (Omron). Aer
obtaining a short medical history, resting energy
expenditure (REE) and respiratory quotient (RQ)
were measured in all participants using an indirect
calorimetry (Ergostik, Geratherm Respiratory
GmbH, Bad Kissingen, Germany) performed with
a face mask with ow sensor. e measurements
were performed in a comfortable and thermoneutral
environment with attention to standardized resting
conditions and exclusion of possible distractions.
Data from the indirect calorimetry and the estimated
daily energy expenditure were used to calculate the
desired caloric intake. Cubital vein was cannulated
for blood sampling. e subjects underwent an oral
glucose tolerance test (OGTT). Aer the rst baseline
blood sampling (0 min), the participants ingested a
solution of 75 g glucose in 250 ml water within 3 min.
Blood samples were collected in 30 min intervals for
2 h into polyethylene tubes, processed, and serum
and plasma aliquots stored at –70°C until analyzed.
Cardiorespiratory tness, expressed as maximal
oxygen consumption (VO2max), was measured using
the ramp protocol as described previously (Bajer et
al. 2019).
118 Irisin and BDNF response to 8-weeks lifestyle intervention
Biochemical analyses and calculations. All
standard biochemical parameters (glucose, insulin,
lipid parameters, etc.) were assayed in certied
hospital laboratory (Synlab Bratislava, Slovakia) using
appropriate methods on auto-analyzer Beckman
Coulter AU (Beckman Coulter, Inc., Brea, CA, USA).
Serum insulin concentrations were measured using
Chemiluminescent Microparticle Immunoassay
(CMIA; ARCHITECT Immunoassay analyzer,
Abbott Laboratories Diagnostics, Lake Forest, IL,
USA). Irisin concentration was measured in plasma
aer 10-fold dilution of the sample according to the
manufacturer’s recommendation for optimal dilution
for the particular experiments using the Human
Irisin ELISA Kit (Cusabio, Houston TX, USA) with
declared detection range 3.12–200 ng/ml, intra-assay
variability <8% and inter-assay variability <10%.
BDNF concentrations were measured in plasma using
the Human BDNF ELISA Kit (Cusabio, Houston TX,
USA) with declared detection range 0.3125–20 ng/ml,
intra-assay variability <8% and inter-assay variability
<10%. (Cusabio, Houston TX, USA).
Insulin sensitivity/resistance indices were
calculated using fasting (HOMA-IR, Matthews et
al. 1985) and OGTT-derived serum glucose and
insulin concentrations (ISICed, Cederholm and Wibell
1990; ISIMat, Matsuda and DeFronzo 1999). Insulin
response to oral glucose load was calculated as Area
Under the Curve (AUC) using the trapezoidal rule.
e fatty liver index (FLI) was calculated according
to the formula proposed by Bedogni et al. (2006)
using gamma-glutamyl transferase (GGT), BMI,
triglycerides, and waist circumference as variables,
with FLI<30 representing low likelihood and FLI≥60
high likelihood of having hepatic steatosis (Bedogni
et al. 2006).
Intervention. e intervention of the participants
has been described previously (Bajer et al. 2019).
Briey, the subjects underwent an 8-week weight loss
intervention program including reduction of caloric
intake by 30% of the weight maintenance calories and
150 min per week of moderate to intensive aerobic
exercise. e investigators provided individual
detailed instructions and counseling about lifestyle
changes: personalized nutritional plan prepared
using soware PLANEAT (www.planeat.sk) and
individually tailored plan of physical activity (type,
duration, frequency, repetitions). e creation of the
personalized nutrition plans and plans for individu-
ally tailored physical activity have been described
previously (Bajer et al. 2019).
Statistical evaluation. Statistical analysis of the
data was performed using the IBM SPSS Statistics
version 19 (SPSS Inc., Chicago, IL, USA). e pre- and
post-dierences in the mean values were analyzed
by the Student’s paired t-test or the Wilcoxon
signed-rank test depending on the normality of
the data distributions, which was assessed by the
Kolmogorov-Smirnov test. e general linear model
(repeated measures analysis of variance, ANOVA)
with Student-Newman-Keuls post hoc test was used
to analyze the dierences in plasma insulin response
to oral glucose load during the OGTT before and
aer the intervention. e associations of irisin and
BDNF with other anthropometric and cardiometa-
bolic parameters measured were examined using
Pearson’s or Spearman’s correlation depending on
the normality of data. Normally distributed data
were expressed as mean±SD, while data not normally
distributed were expressed as median (interquartile
range [IQR]). A p value less than 0.05 was considered
to be statistically signicant.
Results
e whole group of participants. e available
samples of 37 participants (10 men and 27 women)
with the mean age of 44.5±12.0 years were used to
examine the eect of 8-weeks lifestyle interven-
tion program on the cardiometabolic parameters.
Anthropometric, clinical, and laboratory character-
istic of the study participants before and aer inter-
vention are presented in Table 1.
As expected, the evaluated cardiometabolic
parameters improved signicantly overall. Aer
8 weeks of the lifestyle intervention program, the
participants in the whole observed group had
signicantly lower BMI, percentage of the body fat,
blood pressure, insulin resistance and lipid and liver
parameters. Physical tness, expressed as VO2max,
improved as well in all subjects (Table 1).
Plasma glucose concentration course during
OGTT was comparable before and aer the lifestyle
intervention program (Figure 1A). e insulin
response to the oral glucose load was signicantly
lower aer intervention (F=16.3; p<0.001) in all
subjects evaluated, as shown in Figure 1B.
Irisin levels decreased signicantly (p<0.001) aer
the lifestyle intervention (Figure 2A), while BDNF
levels increased, however, this increase did not reach
statistical signicance (p=0.114) (Figure 2B) in all
examined subjects.
e lower-weight-loss (LWL) subgroup. From 37
volunteers, who completed the intervention study and
had sucient number of samples for all analyses, we
identied a subgroup of 17 participants (3 men and
119R, et al.
14 women with the mean age 46.2±11.4 years), who
lost ≤5% of their initial body weight and considered
their weight loss insucient. eir characteristics are
presented in Table 2.
Even the lower-than-expected weight loss was
signicant and accompanied by a signicant
reduction in body fat percentage, several cardiometa-
bolic parameters also improved aer intervention,
particularly the systolic blood pressure, fasting and
post-load insulin levels as well as FLI, a marker of
the fatty liver. e improvement in physical tness
(VO2max) did not reach statistical signicance
(Table2).
In the LWL subgroup, plasma glucose concentra-
tion course during OGTT was comparable before
and aer the intervention program (Figure 1C). e
response of insulin to oral glucose load was signi-
cantly lower aer intervention even in the LWL
subgroup (F=8.8; p=0.009, Figure 1D), which reects
the improvement of insulin sensitivity, even the
increments in calculated insulin sensitivity indices
did not reach statistical signicance (Table 2).
Like in the whole participants group, irisin
levels decreased signicantly (p=0.002) in the LWL
subgroup (Figure 2C) aer lifestyle intervention
program. Remarkably, although the increase in
Table 1
General characteristics of all participants before and aer 8 weeks of intervention
Parameter Before intervention
(n=37)
Aer intervention
(n=37) p-value
BMI (kg/m2) 30.5±4.8 28.6±4.6 <0.001
Body fat (%) 34.8 (31.9–40.6) 31.6 (27.0–36.4) <0.001
Waist (cm) 98±14 91±12 <0.001
Hip (cm) 111±11 107±10 <0.001
BPsys (mmHg) 125 (116–136) 114 (109–129) <0.001
BPdia (mmHg) 76±12 72±9 =0.008
Heart rate (1/min) 74±14 70±11 =0.032
Fasting glucose (mmol/l) 4.3±0.6 4.2±0.5 =0.339
Fasting insulin (mIU/l) 7.3 (5.1–9.4) 4.9 (3.7–6.9) <0.001
HOMA-IR 1.32 (0.90–1.85) 0.86 (0.64–1.37) <0.001
ISI Cederholm 60±21 62±19 =0.324
ISI Matsuda 7.0±4.2 8.6±3.7 =0.002
AUC insulin 6534 (4083–9998) 5295 (3338–7274) =0.015
AST (kat/l) 0.37±0.12 0.35±0.09 =0.168
ALT (kat/l) 0.30 (0.23–0.41) 0.26 (0.21–0.39) =0.005
GGT (kat/l) 0.27 (0.21–0.38) 0.23 (0.20–0.31) =0.014
FLI 45.2±30.4 29.8±22.7 <0.001
Total cholesterol (mmol/l) 5.16±1.35 4.73±1.04 =0.005
HDL-C (mmol/l) 1.45±0.37 1.38±0.30 =0.066
LDL-C (mmol/l) 3.22 (2.56–3.92) 2.77 (2.41–3.55) =0.024
Triglycerides (mmol/l) 0.94 (0.62–1.40) 0.79 (0.59–1.13) =0.045
VO2max (ml/(kg.min)) 25.5±5.9 29.2±5.6 <0.001
Irisin (ng/ml) 236±58 165±79 <0.001
BDNF (ng/ml) 2.56±1.43 3.27±2.63 =0.114
Data are presented as means±SD for parametric variables and median (interquartile range) for nonparametric variables, depending on
normality testing. Respective statistical tests are used to express the p-value (Student’s paired t-test or the Wilcoxon signed rank test).
Abbreviations: AUC – area under curve; BDNF – brain-derived neurotrophic factor; BMI – body mass index; BPdia – blood pressure
diastolic; BPsys – blood pressure systolic; FLI – fatty liver index; GGT – gamma-glutamyl transferase; HDL-C – high-density
lipoprotein-cholesterol; HOMA-IR – Homeostatic Model Assessment for Insulin Resistance; LDL-C – low-density lipoprotein-
cholesterol.
120 Irisin and BDNF response to 8-weeks lifestyle intervention
BDNF following the lifestyle modication was not
signicant in the whole participants group, in the
LWL subgroup, a signicant BDNF increase (p=0.038)
aer intervention was observed (Figure 2D).
e gender and the age impact. When analyzing
the entire dataset for males and females separately,
the pattern of cardiometabolic improvement was
comparable in both sexes. ere were no signicant
dierences when comparing the changes (deltas) of
irisin (p=0.691) and BDNF (p=0.919) aer lifestyle
intervention between sexes. e men improved
signicantly in several liver parameters (alanine
transaminase – ALT, GGT, FLI), whereas the women
in FLI only. In the women, the improvement in FLI
reached a lesser extent (p=0.025), probably due to
markedly lower initial FLI values.
Being aware of the wide age range of our subjects,
we compared the irisin and BDNF levels between
the subgroups of individuals younger than 47 years
(Y; n=19) and older than 47 years (O; n=18). e
decrease of irisin aer intervention was signicant in
both age groups (Y: 238±58 ng/ml vs. 162±78 ng/ml,
p<0.001; O: 232±60 ng/ml vs. 168±84 ng/ml, p<0.001)
and comparable (delta irisin Y: –76±61 ng/ml vs. O:
–64±53 ng/ml, p=0.570). e increase of BDNF aer
intervention was not signicant in both age groups
(Y: 2.50±1.42 ng/ml vs. 3.34±2.82 ng/ml, p=0.271; O:
2.63±1.48 ng/ml vs. 3.18±2.48 ng/ml, p=0.325) and
comparable (delta BDNF Y: 0.85±2.80 ng/ml vs. O:
0.55±2.00 ng/ml, p=0.739).
Correlation analyses demonstrated that the
changes in irisin levels were positively correlated
Figure 1. Plasma glucose (A) and insulin (B) concentrations of the oral glucose tolerance test before
and aer the intervention in the whole group of volunteers (n=37) and plasma glucose (C) and insulin
(D) concentrations of the oral glucose tolerance test before and aer the intervention in the lower-
than-expected weight loss subgroup of volunteers (n=17). Data are presented as mean±SD. Figure 1B
– ###p<0.001 between pre- and post-intervention (p<0.001, F=16.305); *p<0.05, **p<0.01, ***p<0.001
for Student-Newman-Keuls post hoc comparisons between pre- and post-intervention data within in-
dividual sampling times. Figure 1D – ##p<0.01 between pre- and post-intervention (p=0.009, F=8.787);
*p<0.05 for Student-Newman-Keuls post hoc comparisons between pre- and post-intervention data
within individual sampling times.
121R, et al.
with the changes in the weight (r=0.456, p=0.007),
BMI (r=0.473, p=0.005), and percentage of body fat
(r=0.345, p=0.046) and negatively correlated with
changes in whole-body insulin sensitivity expressed
as ISI Matsuda (r=–0.409, p=0.02) and with
improvement in physical tness expressed as VO2max
(r=–0.532, p=0.007). Changes in plasma BDNF levels
were negatively correlated with changes in systolic
blood pressure (r=–0.361, p=0.036) and positively
with changes in the peripheral insulin sensitivity
expressed as ISI Cederholm (r=0.416, p=0.012). No
correlation of BDNF with parameters of the obesity
(BMI, body fat percentage, waist circumference) or
with irisin levels was observed. No signicant mutual
correlation of parameters of interest (irisin and
BDNF), their initial, post-interventional levels or even
their changes over time was found (p=0.256–0.800).
Discussion
e present study was aimed to assess the irisin
and BDNF levels on the background of improvement
of cardiometabolic status in response to the life style
counseling in the overweight/obese subjects with the
sedentary lifestyle. In our 8-week follow-up study,
the participating sedentary subjects lost weight and
Table 2
General characteristics of participants of the lower-weight-loss (LWL) subgroup before and aer 8 weeks of intervention
Parameter Before intervention
(n=17)
Aer intervention
(n=17) p-value
BMI (kg/m2) 29.3±4.4 28.4±4.5 <0.001
Body fat (%) 34.5 (31.1–40.0) 32.0 (28.1–37.4) <0.001
Waist (cm) 91 (84–102) 88 (80–98) <0.001
Hip (cm) 109±8 106±8 =0.003
BPsys (mmHg) 127±12 118±11 =0.007
BPdia (mmHg) 77±8 73±6 =0.115
Heart rate (1/min) 74±12 72±9 =0.520
Fasting glucose (mmol/l) 4.2±0.4 4.2±0.5 =0.850
Fasting insulin (mIU/l) 6.3 (5.7–8.3) 5.7 (4.0–6.9) =0.021
HOMA-IR 1.23 (0.98–1.63) 1.06 (0.72–1.40) =0.074
ISI Cederholm 59±20 62±21 =0.305
ISI Matsuda 6.8±4.5 7.8±3.4 =0.152
AUC insulin 7506 (5063–11128) 6339 (3950–7520) =0.027
AST (kat/l) 0.36±0.10 0.35±0.11 =0.460
ALT (kat/l) 0.36±0.19 0.31±0.19 =0.084
GGT (kat/l) 0.28±0.09 0.28±0.08 =0.404
FLI 38.0±24.6 28.6±21.7 =0.003
Total cholesterol (mmol/l) 5.45±1.57 5.24±1.18 =0.271
HDL-C (mmol/l) 1.55±0.44 1.52±0.35 =0.569
LDL-C (mmol/l) 3.28 (2.45–3.84) 3.01 (2.60–3.99) =0.940
Triglycerides (mmol/l) 1.09 (0.72–1.56) 1.11 (0.57–1.42) =0.562
VO2max (ml/(kg.min)) 25.2±6.5 26.9±4.9 =0.091
Irisin (ng/ml) 234±61 187±79 =0.002
BDNF (ng/ml) 2.38±1.41 3.46±2.44 =0.038
Data are presented as mean±SD for parametric variables and median (interquartile range) for nonparametric variables, depending on
normality testing. Respective statistical tests are used to express the p-value (Student’s paired t-test or the Wilcoxon signed rank test).
Abbreviations: AUC – area under curve; BMI – body mass index; BPsys – blood pressure systolic; BPdia – blood pressure diastolic;
BDNF – brain-derived neurotrophic factor; FLI – fatty liver index; GGT – gamma-glutamyl transferase; HDL-C – high-density
lipoprotein-cholesterol; HOMA-IR – Homeostatic Model Assessment for Insulin Resistance; LDL-C – low-density lipoprotein-choles-
terol.
122 Irisin and BDNF response to 8-weeks lifestyle intervention
favorable changes occurred in metabolic and cardio-
vascular parameters. ese changes were observed
even in a subgroup of participants who lost 5% or less
of their initial body weight. Aer 8 weeks of lifestyle
intervention, serum irisin levels decreased and
correlated with the decrease in the adiposity markers
and the increase of the insulin resistance.
It is generally accepted that lifestyle changes play
a key role in both the prevention and treatment
of obesity and metabolic syndrome (Bajer et al.
2015). e approaches used in the management
of the obesity include changes in dietary habits,
physical activity, and behavioral modications.
Regular exercise has a benecial eect on both the
cardiometabolic parameters and the mental health
(cognitive functions, sleep, mood, etc.) and is known
to counteract in the development of obesity, diabetes,
cardiovascular diseases, etc. (Ball 2015).
e sedentary lifestyle leads to insulin resistance,
dyslipidemia, decreased muscle mass, and increased
visceral adipose tissue. It also increases the risk
of many diseases, such as T2DM, cardiovascular
disease, cancers, etc. Several mechanisms have been
assumed to trigger the benecial eects of physical
activity, such as improved cardiorespiratory tness
(VO2max), decreased adiposity and circulating
lipids, decrease in inammatory parameters, energy
expenditure, and weight loss (Whitham and Febbraio
2016).
e FLI (Bedogni et al. 2006) is a validated
biomarker for the diagnosis of fatty liver (Foschi et al.
2021) and its levels ≥60 can identify not only subjects
with the liver steatosis, but also a high cardiometa-
bolic risk (Carli et al. 2023). Our lifestyle intervention
led to a signicant decrease of this parameter. is
means that in 38% of study participants high risk of
Figure 2. Plasma irisin (A) and brain-derived neurotrophic factor (BDNF) (B) concentrations before
and aer the intervention in the whole group of volunteers (n=37) and plasma irisin (C) and BDNF
(D) before and aer the intervention in the lower-than-expected weight loss subgroup of volunteers
(n=17). Box-and-whisker plots represent mean and SD. *p<0.05; **p<0.01; ***p<0.001 between pre
and post intervention.
123R, et al.
liver steatosis was identied in the initial examina-
tions. However, aer intervention, the percentage
of subjects with high risk decreased to 8%. Similar
pattern was observed in the LWL subgroup, where
the percentage of subjects with high liver steatosis
risk decreased from 24% to 12% aer intervention.
Besides the positive eect of exercise on the cardio-
metabolic status, physical activity has been suggested
to improve sleep, memory, cognitive functions,
dementia, and depression by increased BDNF
production (Inyushkin et al. 2023). In our study, we
did not nd any signicant changes in plasma BDNF
levels aer intervention program or its correlation
with the age or obesity markers. Several human
studies have been focused on the changes in BDNF
levels in subjects with/without obesity, depending
on the intensity and duration of the physical activity
as well as the age of the participants. Acute exercise
leads to a transient increase in serum BDNF concen-
trations in healthy active males (Rojas Vega et al.
2006) and active and sedentary females (Nofuji et
al. 2012). However, some authors have reported a
transient elevation of circulating BDNF levels in the
elderly sedentary/inactive, but not active elderly or
young individuals (Maderova et al. 2019), especially
women (Alizadeh and Dehghanizade 2022).
On the other hand, there are inconsistent data
regarding the baseline levels in active vs. sedentary,
obese vs. non-obese individuals or regarding the
eect of long-term training program on BDNF
levels. ree-month training did not induce any
changes in resting serum or plasma BDNF levels in
elderly subjects and those levels were comparable
with young lean active individuals (Maderova et al.
2019). e chronic exercise did not aect the BDNF
levels in the obese children (Rodriguez-Ayllon et
al. 2023). Other authors have found higher baseline
serum BDNF levels in active compared to inactive
obese females (Alizadeh and Dehghanizade 2022) or
even inverse relationship between serum BDNF levels
and physical tness (expressed as VO2max) has been
reported (Currie et al. 2009).
Similarly, reduced circulating BDNF levels have
been reported in obese individuals (Alomari et al.
2020; Katuri et al. 2021). Other authors have reported
increased circulating levels of BDNF in subjects with
obesity (Golden et al. 2010; Slusher et al. 2015). Addi-
tionally, a meta-analysis of ten studies have revealed
comparable circulating BDNF levels in obese and
control subjects (Sandrini et al. 2018). One of the
explanations for the considerable dierences in the
literature could be in representation of dierent
BDNF pools in serum and plasma samples. In serum,
BDNF released from activated platelets during
clotting is present (Maderova et al. 2019) and this
level depends on the clotting time during blood
sample processing (Currie et al. 2009). On the other
hand, plasma levels represent a biologically available
BDNF pool (Maderova et al. 2019). Another point
is that the circulating BDNF levels in the periphery
do not adequately reect the BDNF release from the
CNS, e.g. its main production site (Seifert et al. 2010).
Several authors have suggested that the exercise-
induced irisin stimulates secretion of BDNF in the
brain leading to a cognitive improvement (Jo and
Song 2021; Babaei et al. 2023; Inyushkin et al. 2023).
Our results based on the plasma irisin and BDNF
levels cannot conrm this hypothesis. However, it is
possible that the organokine levels measured in the
peripheral circulation do not adequately reect the
processes in the brain (Seifert et al. 2010).
Bostrom et al. (2012) have discovered irisin as an
exercise-induced myokine cleaved from the trans-
membrane protein bronectin type III domain-
containing 5 (FNDC5) and hypothesized its role
in mediating the positive eects of exercise on
browning of the white adipose tissue, increasing
energy expenditure, weight loss, and improving
glucose metabolism. Several authors have supported
this hypothesis by the nding of increased irisin
levels aer acute exercise bouts but not training or
prolonged exercise (Huh et al. 2012; Kraemer et al.
2014; Norheim et al. 2014). Other authors also failed
to nd signicant changes in circulating irisin
in response to long-term exercise (Hecksteden et
al. 2013; Pekkala et al. 2013; Kurdiova et al. 2014;
Miazgowski et al. 2021).
Only few years aer the discovery of irisin and
postulating its features as a skeletal muscle-derived
exerkine responsible for metabolic improvement
(Bostrom et al. 2012), the antibodies used for its
detection in several studies have been investigated in
detail (Albrecht et al. 2015). e research revealed that
in more than 80 studies, the methods used to detect
irisin did not measure irisin itself, but some other
cross-reacting proteins. e amino acid sequence,
which was the target of antibodies used in the kits,
was actually not part of the circulating irisin, not
even in the case of the original study (Albrecht et al.
2015). However, this did not eliminate the discrepan-
cies in the exercise-induced irisin secretion pattern.
ere were several attempts to elucidate the contra-
dictory data reported, e.g. the lack of validation of
detection methods used to report irisin concen-
trations with variations by order of magnitude
(0.01–2000 ng/ml), presence of glycosylated irisin
124 Irisin and BDNF response to 8-weeks lifestyle intervention
molecule (Albrecht et al. 2015; Gamas et al. 2015;
Maak et al. 2021). Irisin over-time degradation in
frozen samples obtained before exercise intervention
led to a false increase of irisin levels aer several weeks
of training (Hecksteden et al. 2013) or the mutation of
the start codon of the gene encoding the precursor of
irisin present in humans, but not rodents (Raschke et
al. 2013), were suspected as well. Other authors have
suggested dierent spectrum of myokines secreted
from the insulin-resistant and insulin-sensitive
exercising skeletal muscles (Kurdiova et al. 2014)
supporting the hypothesis of irisin downregulation
in the insulin-resistant muscle.
e nding that chronic exercise is not related to
the increased irisin levels, led to a suggestion of a
presence of an adaptive mechanism in active subjects,
making them more sensitive to irisin action (Huh et
al. 2014; Gamas et al. 2015). e controversies are
even more prominent when it comes to irisin concen-
trations in relation to obesity, insulin resistance, and
other pathological conditions (Perakakis et al. 2017;
Polyzos et al. 2018).
Besides skeletal muscles, the adipose tissue is
the second most important site of irisin secretion
(Perakakis et al. 2017), however, only with a minor
contribution to the circulating pool (Huh et al. 2012;
Kurdiova et al. 2014), which however, might become
substantial in obesity due to higher fat mass (Polyzos
et al. 2018). Dierent regulation of irisin secretion
has been assumed in obesity or metabolic disar-
rangement (Gamas et al. 2015). Considering irisin an
exercise-induced myokine, the ndings of increased
irisin levels in the subjects with obesity, insulin
resistance, metabolic syndrome, and associated
features are against all odds. Several studies have
described a positive association of irisin levels and
markers of obesity, such as BMI, body fat percentage,
waist circumference (Crujeiras et al. 2015; Polyzos et
al. 2018; Jia et al. 2019; Gonzalez-Gil and Elizondo-
Montemayor 2020) or have reported increased irisin
in metabolic syndrome and its positive association
with insulin resistance and cardiovascular risk (Park
et al. 2013).
Additionally, weight loss achieved either by energy
restriction, surgical intervention (Crujeiras et al.
2015) or dietary and physical activity interventions
(Tok et al. 2021) led to decreased irisin concentrations
in circulation. Similarly, we also found a positive
correlation between changes in irisin levels and
changes in body composition (BMI, weight, body fat
percentage), although our subjects were not extremely
obese, but predominantly sedentary. Furthermore,
in our study, the irisin decrease correlated with an
increase in the insulin sensitivity. However, this is not
in agreement with studies that found increased irisin
levels in obese patients following exercise-induced
weight loss (Merawati et al. 2023). is could lead to
an assumption that patients with T2DM could have
even higher levels of irisin. However, several studies
have proven the opposite (Vecchiato et al. 2022)
suggesting chronic hyperglycemia and hyperlipid-
emia being the triggering factor for the “switch” from
high irisin secretion in obesity to low irisin secretion
in T2DM (Perakakis et al. 2017).
A possible explanation for the elevated irisin
levels in obesity might be the development of “irisin
resistance”, similar to insulin or leptin resistance seen
in obese subjects (Parks et al. 2013). Elevated irisin in
the obesity and metabolic syndrome might be seen
as a compensatory mechanism aimed at overcoming
the irisin resistance, maximizing energy usage, and
achieving metabolic homeostasis (Perakakis et al.
2017; Arhire et al. 2019).
Some studies have reported association of
circulating irisin levels with age, however, with
opposite outcomes (Trettel et al. 2023), e.g. baseline
irisin levels have been reported to be lower in older
individuals (Huh et al. 2014) or a positive correlation
between age and irisin levels in plasma and cerebro-
spinal uid has been reported (Ruan et al. 2019). We
did not observe any relationship of irisin levels with
age, even having a broad age range (20–69 years) of
our participants. erefore, we assume that the age
itself is not the one of the main factors inuencing the
circulating irisin levels. Other factors, such as muscle
mass, body fat percentage, physical tness, nutritional
status, accompanying diseases, which strongly
correlate with age, might be better candidates.
Study limitations. e present study outcomes
have some limitations. Subjects of a wide age range
(20–69 years) and an unbalanced gender ratio (10
men, 27 women) were enrolled in the study. However,
we did not observe any impact of gender or age on
the parameters of interest. Regarding the organokine
levels in the periphery, they may not completely
reect the processes in the brain compartments.
Dierent types of exercise were applied according to
the individual preferences (as described by Bajer et
al. 2019). Some participants were taking medications
for comorbidities, which might inuence the study
results. Finally, dierent adherence of our partici-
pants to the intervention program might also aect
the data.
Conclusions. e regulation of irisin secretion
and its action is not that simply like in rodents and
many other variables may inuence the irisin levels in
125R, et al.
humans. us, the age, sex, body composition, health
status, and type of duration, frequency, and intensity
of physical activity may play a substantial role (Huh
et al. 2014; Buscemi et al. 2018; Gonzalez-Gil and
Elizondo-Montemayor 2020). e lifestyle interven-
tion, including the diet and the physical activity, is an
eective way to improve the cardiometabolic status.
e nding of decreased irisin aer intervention and
its correlations with markers of adiposity support
the hypothesis of the presence of “irisin resistance”.
e lifestyle changes, even without remarkable
weight loss, were able to induce positive cardiometa-
bolic changes in sedentary subjects, which leads to
the assumption that health benets of the lifestyle
changes exceed the benets of weight loss alone. is
supports the current theory that physical inactivity
is being one of the leading risk factors of the cardio-
vascular diseases. However, the exact mechanisms of
irisin secretion and action need to be further studied.
Acknowledgement
e authors express appreciation to the volunteers
for their participation in the study. e study was
supported by the grants: APVV-22-0047 (Slovak
Research and Development Agency) and VEGA
2/0105/24.
Conict of interest: e authors declare no conict
of interest.
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