J C E M
O N L I N E
B r i e f
R e p o r t — E n d o c r i n e
R e s e a r c h
Adipose Tissue Secretion and Expression of AdipocyteProduced and Stromavascular Fraction-Produced
Adipokines Vary during Multiple Phases of WeightReducing Dietary Intervention in Obese Women
Michaela Siklova-Vitkova, Eva Klimcakova, Jan Polak, Zuzana Kovacova,
Michaela Tencerova, Lenka Rossmeislova, Magda Bajzova, Dominique Langin,
and Vladimir Stich
Franco-Czech Laboratory for Clinical Research on Obesity (M.S.-V., E.K., Z.K., M.T., L.R., M.B., D.L.,
V.S.), Third Faculty of Medicine, Prague, CZ-100 00, Czech Republic, and Institut National de la Santé et
de la Recherche Médicale 31232, Toulouse, France; Laboratory of Clinical Biochemistry (D.L.), Toulouse
University Hospitals, 31059 Toulouse, France; Department of Sport Medicine (M.S.-V., E.K., J.P., Z.K.,
M.T., L.R., M.B., V.S.), Third Faculty of Medicine, Charles University, Prague, CZ-100 00 Czech Republic;
Institut National de la Santé et de la Recherche Médicale, Unité 1048 (D.L.), Obesity Research
Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC); University of Toulouse (D.L.), Paul
Sabatier University, F-31432 Toulouse, France; and 2nd Internal Medicine Department (J.P.), Vinohrady
Teaching Hospital, CZ-100 34 Prague, Czech Republic
Context: Obesity is associated with altered plasma levels of adipokines involved in the development
of insulin resistance and obesity-related metabolic disturbances.
Objective: The aim was to investigate diet-induced changes in adipokine production in sc abdominal adipose tissue (SAT) during a 6-month, multiphase, weight-reducing dietary intervention.
Design, Setting, Participants, and Interventions: Forty-eight obese women followed a dietary intervention consisting of a very low-calorie diet (VLCD) (1 month), followed by a weight-stabilization (WS)
period, which consisted of a low-calorie diet (2 months), and a weight-maintenance diet (3 months).
Main Outcome Measures: Before and at the end of the VLCD and WS, samples of plasma and SAT
were obtained. In a subgroup of 26 women, secretion of adipokines was determined in SAT explants, and in a subgroup of 22 women, SAT mRNA expression was measured.
Results: Body weight decreased and insulin sensitivity increased during the intervention. Plasma
levels, SAT mRNA expression, and secretion rates of adipocyte-produced adipokines (leptin, serum
amyloid A, and haptoglobin) decreased during the VLCD and increased during the WS period.
Adipokines produced mainly from stroma-vascular cells (IL-6, IL-8, IL-10, IL-1Ra, TNF␣, plasminogen
activator inhibitor-1, and monocyte chemoattractant protein-1) increased or remained unchanged
during VLCD and decreased to levels equal to or lower than prediet levels during the WS period.
The diet-induced changes in homeostasis model assessment of insulin resistance correlated with
changes in leptin plasma levels during VLCD, WS, and the entire dietary intervention period.
Conclusions: Diet-induced regulation of adipokine production in SAT differs according to their
cellular origin (adipocytes vs. stroma-vascular cells) and diet phase (VLCD vs. WS). Insulin-sensitivity
changes were associated only with those of plasma leptin. (J Clin Endocrinol Metab 97:
E1176 –E1181, 2012)
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2380 Received August 24, 2011. Accepted March 26, 2012.
First Published Online April 24, 2012
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jcem.endojournals.org
Abbreviations: AT, Adipose tissue; BMI, body mass index; CRP, C-reactive protein; DI,
dietary intervention; FM, fat mass; HGF, hepatocyte growth factor; HOMA-IR, homeostasis
model assessment of insulin resistance; MCP-1, monocyte chemoattractant protein 1;
NEFA, nonesterified fatty acid; PAI-1, plasminogen activator inhibitor 1; SAA, serum amyloid A; SAT, sc abdominal adipose tissue; SVF, stroma-vascular fraction; VLCD, very lowcaloric diet; WS, weight stabilization.
J Clin Endocrinol Metab, July 2012, 97(7):E1176 –E1181
J Clin Endocrinol Metab, July 2012, 97(7):E1176 –E1181
besity is associated with the development of metabolic and cardiovascular diseases. A number of bioactive molecules produced by adipose tissue (AT), such as
cytokines, chemokines, and acute phase proteins, known
as adipokines, have been suggested as a possible link between obesity and insulin resistance (1).
Different cell types in AT produce different adipokines.
Adipokines produced mainly by adipocytes include leptin,
adiponectin, haptoglobin, and serum amyloid A (SAA) (2,
3), whereas adipokines produced mainly by cells of the
stroma-vascular fraction (SVF) include TNF␣, IL-6, IL10, IL-8, monocyte chemoattractant protein-1 (MCP-1),
and plasminogen activator inhibitor 1 (PAI-1) (1, 4).
It has been hypothesized that the beneficial effects of
lifestyle interventions in the treatment of obesity might be
mediated by modification of the secretory profile and/or
mRNA expression of adipokines in AT and reduction of
systemic inflammation. However, previous studies have
yielded inconsistent results (5).
In the present study, we investigated the mRNA expression and plasma levels of adipokines produced by adipocytes and SVF of AT at several time points during a
6-month, multiphase, weight-reducing dietary intervention (DI). In addition, we investigated the evolution of
adipokine secretion from biopsy-derived explants of sc
abdominal adipose tissue (SAT). The relationship between
diet-induced changes of adipokines characteristics and improved insulin sensitivity was also explored.
O
Subjects and Methods
Subjects
Forty-eight obese, premenopausal, women (aged 35 ⫾ 7 yr,
range 22–51 yr) were recruited at the Third Faculty of Medicine, Charles University, Prague, Czech Republic. Exclusion
criteria were a change in body weight greater than 3 kg within
the 3 months preceding the study, diabetes, drug-treated obesity, pregnancy, participation in other trials, and alcohol or
drug abuse. Volunteers gave written informed consents, and
the study was approved by the Ethics Committee of the Third
Faculty of Medicine.
jcem.endojournals.org
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frozen at ⫺80 C and stored until mRNA expression analysis. In
group 2 (n ⫽ 26), AT was used immediately to assess secretion
of adipokines in the biopsy samples (explants). Insulin resistance
was assessed using homeostasis model assessment of insulin resistance (HOMA-IR) [(fasting blood glucose [millimoles per liter] ⫻ fasting insulin [milliunits per liter])/22.5].
In vitro adipose tissue secretion
Secretion from SAT explants was investigated as described
previously (7, 8). Briefly, 400 mg of AT explants was incubated
in 4 ml of Krebs/Ringer phosphate buffer (pH 7.4) supplemented
with 40 g/liter of BSA and 1 g/liter of glucose for 4 h at 37 C. Then
200 ␮l aliquots of medium were stored at ⫺80 C until analysis.
The explants were used for total DNA content measurement
(MasterPure DNA purification kit; Epicenter Biotechnologies,
Madison, WI).
Media and plasma analysis
Nonesterified fatty acid (NEFA) levels were determined using
an enzymatic procedure (Wako, Richmond, VA). Plasma levels
of glucose, insulin, and C-reactive protein (CRP) were determined using standard methods. Plasma and conditioned media
levels of adipokines were determined using multiplex human
cytokine and adipocyte Milliplex panels (Millipore-Merck, Bedford, MA). IL-1Ra was measured with ELISA (R&D Systems,
Minneapolis, MN).
RNA analysis
Total RNA was isolated as previously described (6). mRNA
expression of 13 genes (ADIPOQ, LEP, IL1B, IL6, IL8, TNF,
CCL2, SERPIN1, HGF, IL-1RN, IL10, SAA1, haptoglobin)
were assessed using quantitative PCR with a sequence detection
system (ABI PRISM 7900; Applied Biosystems, Foster City, CA)
and custom TaqMan low-density arrays with TaqMan gene expression assays (Applied Biosystems) (Supplemental Table 1,
published on The Endocrine Society’s Journals Online web site
at http://jcem.endojournals.org). Ribosomal 18S RNA was used
as an endogenous control. Results are expressed as 2⌬Ct values.
Statistical analysis
Data were log transformed and analyzed using SPSS version
13.0 software (SPSS Inc., Chicago, IL). ANOVA with repetitive
measures was used for analysis of diet-induced evolution of clinical data, mRNA, media, and plasma levels. Correlations of dietinduced relative changes between adipokines and clinical characteristics during VLCD, WS, and whole DI were performed
using the Pearson’s parametric test.
Dietary intervention and clinical investigation
The DI lasted 6 months. During the first phase (1 month),
participants followed a very-low caloric diet (VLCD) of 800
kcal/d (liquid formula diet; Redita, Promil, Czech Republic). The
subsequent weight-stabilization (WS) period consisted of a lowcalorie diet (2 months; 600 kcal/d less than the estimated energy
requirement) and a weight-maintenance diet (3 months).
Patient examinations including anthropometry, blood sampling, and needle biopsy of SAT [performed under local anesthesia in the abdominal region as previously reported (6)] were
done in a fasting state before the start of the DI, after VLCD and
again after WS. For the AT investigation, the participants were
alternately divided into two groups. In group 1 (n ⫽ 22), AT was
Results
Clinical characteristics
Clinical data of all participants before DI (baseline) and
during DI are shown in Table 1. When compared with
baseline, body weight decreased by 7.7% during VLCD
and by 11.1% after WS. Body mass index (BMI), fat mass
(FM), and waist circumference showed a similar pattern of
change. HOMA-IR decreased during VLCD, and the reduction was still present at the end of the WS phase.
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Siklova-Vitkova et al.
Adipokines in AT during Dietary Intervention
TABLE 1. Clinical parameters of 48 obese women
before and at the end of different phases of multiphase
dietary intervention
Parameter
Before diet
Weight (kg)
95.9 ⫾ 12.5
BMI (kg/m2)
34.8 ⫾ 3.8
FM (kg)
40.2 ⫾ 8.8
Fat-free mass
56.3 ⫾ 5.8
(kg)
Waist (cm)
103.7 ⫾ 9.5
Glucose
5.24 ⫾ 0.52
(mmol/liter)
Insulin (mU/liter) 12.4 ⫾ 6.7
Glycerol
170 ⫾ 81
(␮mol/liter)
NEFA
740 ⫾ 277
(␮mol/liter)
Triglycerides
1.5 ⫾ 0.7
(mmol/liter)
Total cholesterol
5.0 ⫾ 0.8
(mmol/liter)
HDL (mmol/liter)
1.3 ⫾ 0.4
hs-CRP
5.5 ⫾ 0.9
(mg/liter)
HOMA-IR
2.9 ⫾ 1.7
After VLCD
88.5 ⫾ 12.0a
32.1 ⫾ 3.6a
34.7 ⫾ 8.2a
54.1 ⫾ 6.2
After WS
85.3 ⫾ 12.4b
30.9 ⫾ 3.8b
31.4 ⫾ 8.6b
53.7 ⫾ 6.0c
97.1 ⫾ 9.9a 94.5 ⫾ 9.7b
4.97 ⫾ 0.59c 5.02 ⫾ 0.60
7.2 ⫾ 3.5b
128 ⫾ 48a
7.7 ⫾ 3.8b
128 ⫾ 64a
924 ⫾ 347a
634 ⫾ 228
1.1 ⫾ 0.3a
1.2 ⫾ 0.5a
4.0 ⫾ 0.7b
4.9 ⫾ 0.8
1.1 ⫾ 0.3b
2.7 ⫾ 0.5a
1.4 ⫾ 0.3
2.9 ⫾ 0.4b
1.6 ⫾ 0.8b
1.7 ⫾ 0.9b
Values are means ⫾ SD. HDL, High-density lipoprotein; hs-CRP, highsensitivity CRP.
a
P ⬍ 0.01 compared with baseline values (paired t test).
b
P ⬍ 0.001 compared with baseline values (paired t test).
c
P ⬍ 0.05 compared with baseline values (paired t test).
mRNA expression of adipokines
Adipocyte-produced adipokines (Fig. 1A and Supplemental Table 2)
mRNA expression of SAA and haptoglobin decreased after VLCD and increased thereafter, ultimately
returning to baseline. Leptin mRNA levels decreased
during VLCD and remained lower than prediet values at
the end of WS. Adiponectin mRNA expression was unchanged during the DI.
SVF-produced adipokines (Fig. 1B and Supplemental
Table 2)
mRNA levels of IL-1Ra and hepatocyte growth factor
(HGF) increased during VLCD and returned to baseline by
the end of WS. IL-10 expression was up-regulated during
VLCD but decreased below baseline values after WS. IL-6,
PAI-1, and MCP-1 mRNA levels were unchanged during
VLCD but decreased below baseline levels during WS.
mRNA levels of IL-1␤, IL-8, and TNF␣ mRNA expression
were unchanged from baseline throughout the DI.
Secretion rate of adipokines
Adipocyte-produced adipokines (Fig. 1A and Supplemental Table 2)
Secretion rate of leptin, SAA, and haptoglobin decreased during VLCD and remained lower than prediet
J Clin Endocrinol Metab, July 2012, 97(7):E1176 –E1181
values at the end of WS. Secretion rates of adiponectin
were unchanged during DI.
SVF-produced adipokines (Fig. 1B and Supplemental
Table 2)
IL-1Ra, IL-10, IL-8, and TNF␣ secretion rates increased during VLCD with a subsequent decrease to
prediet values by the end of WS. MCP-1 secretion rate was
unchanged during VLCD but was lower than baseline by
the end of WS. HGF and PAI-1 secretion rates did not
change during the DI. The IL-1␤ concentrations in the
media were under the limit of detection.
Plasma levels of adipokines
Adipocyte-produced adipokines (Fig. 1A and Supplemental Table 2)
Plasma levels of leptin, SAA, and haptoglobin decreased after VLCD and remained significantly lower at
the end of WS phase compared with prediet conditions.
Plasma adiponectin levels were unchanged during DI.
SVF-produced adipokines (Fig. 1B and Supplemental
Table 2)
Plasma levels of IL-1␤, IL-6, IL-8, IL-10, and HGF were
unchanged during the DI. IL-1Ra and TNF␣ concentrations increased after VLCD but decreased under baseline
by the end of WS. MCP-1 concentrations were unchanged
after VLCD but decreased during WS to values that were
below baseline values. PAI-1 levels declined during VLCD
and remained that way after WS.
Associations
Anthropometric indices
The changes in BMI and FM during the entire DI correlated positively with the diet-induced changes in plasma
leptin, CRP, IL-6, PAI-1, and SAA and with the secretion
rate (r ⫽ 0.563, P ⬍ 0.05) and mRNA levels (r ⫽ 0.563,
P ⬍ 0.05) of leptin (Supplemental Table 3).
Homeostasis model assessment of insulin resistance
The diet-induced changes in HOMA-IR correlated positively with changes in plasma leptin during VLCD and
WS as well as during the entire DI, whereas the correlations with changes in the leptin secretion rate and plasma
SAA were found during DI only (r ⫽ 0.563, P ⬍ 0.05 and
r ⫽ 0.563, P ⬍ 0.05, respectively). Importantly, these correlations persisted after adjustment to the diet-induced
FM changes.
When stratifying groups of subjects according to
HOMA-IR decreases during the entire DI, the subgroup
with smaller HOMA-IR decreases presented lower relative diet-induced decreases in plasma leptin and SAA (Sup-
J Clin Endocrinol Metab, July 2012, 97(7):E1176 –E1181
jcem.endojournals.org
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FIG. 1. Profile of adipocyte-produced (A) and SVF-produced (B) adipokines in SAT (mRNA expression and conditioned media) and in plasma
during multiphase dietary intervention presented as fold change in relation to the baseline values. Data are presented as means ⫾ SE.
plemental Table 4). Similarly, stratification according to
diet-induced decreases in fat mass revealed smaller decreases in plasma leptin, CRP, SAA, PAI-1, secreted leptin,
secreted haptoglobin, and leptin mRNA levels in the subgroup with a smaller diet-induced decreases in fat mass.
Discussion
Our results show that a 6-month, multiphase DI modifies
SAT mRNA expression, secretion rate and plasma levels
of adipokines. The pattern of the diet-induced changes
differed with respect to the phase of DI and to the cellular
origin of the respective adipokine. During initial VLCD,
mRNA expression, secretion rate, and plasma levels of
adipocyte-produced adipokines decreased, except for adiponectin. During the subsequent WS phase, an increase
toward prediet levels was observed. For adipokines produced predominantly from SVF, mRNA expression, and
secretion rate increased or remained unchanged during
VLCD but decreased during the WS phase.
The decrease in the mRNA and plasma levels of adipocyte-produced adipokines (leptin, SAA, haptoglobin) is
in agreement with other studies using low-calorie diets (7,
9 –11). The secretion rate of leptin was found to decrease
during the DI in a single study (7).
Variable diet-induced responses in mRNA expression
of SVF-produced cytokines have been observed in SAT (5,
12–14). Plasma levels of IL-6 and TNF␣ have been investigated in a number of studies, which either reported no
change (5, 9, 15) or a decrease (16 –18) after diet-induced
weight loss. Similarly, decreases or no changes in IL-6,
IL-8, and TNF␣ secretion rates from SAT have been found
(7, 13).
In a recent study, we demonstrated that the regulation
of mRNA expression of many genes is dependent on the
severity and duration of calorie restriction and that the
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Siklova-Vitkova et al.
Adipokines in AT during Dietary Intervention
genes expressed predominantly in adipocytes show a
clearly distinct pattern of regulation from those expressed
predominantly in macrophages (6). mRNA expression responses in the present study are in agreement with the
latter study. Importantly, in the present study, we also
focused on secretory characteristics of adipokines and observed that secretion rates paralleled changes in mRNA
levels.
The up-regulation of proinflammatory cytokines in
SAT during VLCD could be associated with increased
lipolysis as released fatty acids activate proinflammatory pathways through Toll-like receptor 4 signaling
(19). This concept is supported by a study of Kosteli et
al. (20), in which an association between macrophage
recruitment in AT and circulating concentrations of
NEFA or AT lipolysis during caloric restriction was
found in mice. Similarly, we found a correlation between DI-induced changes in plasma NEFA with plasma
MCP-1 and leptin changes (data not shown). These results suggest the overall stimulation of the immune response after VLCD as a putative stress reaction to a
marked calorie restriction. It also supports the potential
interplay between immune cells and adipocytes that
may associate fatty acid metabolism and inflammation.
In this study we did not find an association between an
improvement in insulin sensitivity and decreases in proinflammatory adipokines during the respective dietary
phases. Leptin was the only adipokine whose diet-induced
changes in plasma positively correlated with the changes
in HOMA-IR during VLCD and WS as well as during the
entire DI, even when adjusted for fat mass.
In conclusion, we demonstrate that the regulation of
mRNA expression and secretion of adipokines from SAT
clearly differs between periods of severe calorie restriction
(VLCD) and periods of moderate energy restrictions or
energy balance (WS), and importantly, it differs with respect to the main cellular origin of the adipokines (adipocytes vs. SVF fraction). We observed that diet-induced
changes of insulin sensitivity were related to the changes in
plasma levels of leptin.
Acknowledgments
Address all correspondence and requests for reprints to: Dr. Michaela Siklova-Vitkova, Ph.D., Sport Medicine Department, Third
Faculty of Medicine, Charles University, Ruska 87, CZ-100 00
Prague, Czech Republic. E-mail: [email protected].
This work was supported by Grants IGA NS 10519-3-2009
and IGA NT 11450-3-2010 of the Ministry of Health and
Project MSM 0021620814 of the Ministry of Education of the
Czech Republic; Institut National de la Santé et de la Recherche Médicale, Région Midi-Pyrénées; Integrated Project
J Clin Endocrinol Metab, July 2012, 97(7):E1176 –E1181
Hepatic and Adipose Tissue and Functions in the Metabolic
Syndrome (HEPADIP) (www.hepadip.org), Contract LSHMCT-2005-018734; Integrated Project Molecular Phenotyping to Accelerate Genomic Epidemiology (MOLPAGE)
(www.molpage. org), Contract LSH-2003-1.1.3-1; and Collaborative Project Adipokines as Drug Targets to Combat
Adverse Effects of Excess Adipose Tissue (ADAPT)
(www.adapt-eu.net), Contract HEALTH-F2-2008-2011 00).
Disclosure Summary: The authors have nothing to disclose.
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