Effect of Distinct Lifestyle Interventions On Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial

10.1161/CIRCULATIONAHA.117.
030501
Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools:
The CENTRAL MRI Randomized Controlled Trial
Running Title: Yftach Gepner et al.; Lifestyle Strategies and Fat Depot Mobilization
Yftach Gepner, PhD et al.

Downloaded from http://circ.ahajournals.org/ by RUBELIO CORNEJO on February 8, 2018
The full author list is available on page 19.
AddressHV for Correspondence:

Iris
ris Shai, RD, PhD
The S. Daniel Abraham International Center for Health and Nutrition
Department of Public Health
Faculty of Health Sciences
Ben-Gurion University of the Negev
P.O. Box 653, Beer-Sheva 84105, Israel
Tel:++972-8-647-7449/3
Tel:++
++97
++9722-8-
97 8-64
8-647--7449/3
64
Faxx:++972-8-64 647--76
64 7 37
Fax:++972-8-647-7637/8 3 /8
Email:
Ema
m il: irish@bgu.ac.il
ma irish@bgu.a .ac.iil
Meirr J Stampfer,
Sta
t mp
mpffer, M
MD,
D,, DrPH
DrPHH
Channing Division
Div
i ision off Network Medicine
Brigham and Women’s Hospital
Harvard Medical School
Harvard T.H. Chan School of Public Health
181 Longwood Avenue, Boston, MA 02115
Tel: 617.525.2749
Fax: 617.525.2008
Email: mstampfe@hsph.harvard.edu
1
10.1161/CIRCULATIONAHA.117.030501
Abstract
Background—We aimed to assess whether distinct lifestyle strategies can differentially affect
specific body adipose depots.
Methods—We performed an eighteen-month randomized controlled trial among 278 sedentary
adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored
provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-
carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity
(PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-
distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further
followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver,
pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging.
Results—Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m2), 86%
completed the trial, with good adherence. The LF group preferentially decreased reported fat
intake (-21.0% vs. -11.5% for the MED/LC;P<0.001), and the MED/LC group decreased
reported carbohydrates intake (-39.5%vs. -21.3% for the LF;P<0.001). The PA+ groups
significantly increased the metabolic-equivalents (METs)/week vs. the PA- groups (19.0 vs.
2.1;P
2.1;P=0.009).
0.009). Whereas final f moderate weight loss was indifferent, indifffferent, exercise attenuated d tthe
he waist
circumference rebound with the greatest effect in MED/LCPA+ group (P<0.05). VAT VAT T (-22%),
(-222%
2%), ),
ntra-hepatic (-29%), and Intra-pericardial (-11%) fats declines were higher than ppancreatic
intra-hepatic ancr
ancrea
eati
ea ticc aand
ti nd
femur intermuscular fat
femur fatss (1-2%) loss. Independent of weight loss, PA+ with either diet had a
significantly
ignificantly greater effect f t on on decreasing VAT [mean-of-difference=-6.67cm2;95%CI:(-14.8 to
-
-0.45)
0.45) compared
comp pared with PA ]. The MED/LC diet was superior to LF in decreasing intra-hepatic,
intra-pericardial
ntraa-p
-per
eric
er icar
ardi
ar dial
dia and
annd pancreatic
pancreatic fats (P<0.05 for al all).
ll)). In contrast, re renal-s
renal-sinus
sinus and femoral-
nteermmuscularr ffats
intermuscular ats were
werre not
not
o differentially
dif
iffe
fere
fe rent
re n iall
llyy altered
alterred
ed byby lifestyle
life
fest
fe styl
st ylee interventions,
yl inte
terv
rven
rv entiion
o s, but
but by
by weight
weiight loss
los
osss
per-se.
perr-sse. In multivar
multivariate
riatee mmodels,
odeels,
lss further
f th
fur her adadjusted
djusted d for weight
weeig
i ht loss,
loosss, losing
lo
osing VAT
VA AT or intra-hepatic
intr
trra-hep patic fat
fatt
were
werre
re independently
independden entlly associated
asssociat atted with
with improved
imp
mproved d lipid
liipid
id profile,
pro
rofi
ro file
file, losing
le l singg deep-SAT
lo deepp-SAT A with improved
AT i pr
im proved
insulin
nsulilinn se
li ssensitivity
nssit
itiv
iviity aand
iv ndd llosing
osingg su supe
superficial-SAT
p rf
pe rfic
i iaal-
ic l-SSATT remained
r ma
re maiineded
d nneutral
euutr
tral
al ex
except
xce
cept
pt ooff as
association
sso
sociat
atio
ationn wi
io with
decreased d lleptin.
eptin.
Conclusions—Moderate weight loss alone inadequately reflects the significant lifestyle effects
on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat
depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse
responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle
protocols may uniquely induce fat mobilization from specific anatomical sites.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier:
NCT01530724.
Key Words: obesity; physical exercise; randomized controlled trial; diet; physical activity, fat
depots, ectopic fats
2
Clinical Perspective
What is new?
x In this whole body MRI- assessed trial it was found that Mediterranean diet, rich in
unsaturated fats and low in carbohydrates is superior to low fat diet in mobilizing
specific ectopic fat depots as visceral, hepatic, cardiac and pancreatic fats. Exercise has
an additional independent contribution to visceral fat loss.
x Long-term, persistent, moderate weight loss inadequately reflects the significant
beneficial effects of diet/exercise on fat deposits/depots linked to obesity-associated
cardio-metabolic morbidity.
x Independent of weight loss, visceral and hepatic fat reduction is mainly associated to
improved lipids profile, deep subcutaneous fat loss is associated with improved insulin
resistance and superficial fat loss remains neutral.
x Two distinct patterns were identified: ‘differentially responsive depots’ that were
sensitive to the type of intervention (sites mostly directly related to cardioetabolic health)
andd ‘u
an ‘uni
‘uniformly
n form
rmly responsive depots’, which corresponded on
only too w
weight
eight loss per-se,
irrespective
irrespect
tive off th
thee in
inte
intervention.
terv
terven
rv en
nti
tion
o .
What
at are
are tthe
he clini
clinical
niccall iimplications?
mpl
p ic
icat
atio
ations
ions??
ns
x H
Human ffatt pools
l are hi hl diverse
highly di i their
in th i response tto lif t l iinterventions
lifestyle t ti dduring
i
long-term, moderate weight reduction.
x Currently, guidelines for weight loss rarely consider strategies for organ-specific fat
depots. The CENTRAL trial results may suggest more specific strategic to treat distinct
organs (e.g. for fatty liver, cardiac fat and pancreas).
x As Depot-specific body fat mobilization might be a focus in public health in the future
rather than weight loss alone.
3
Among the different human fat storage pools, visceral adipose tissue (VAT) is most strongly
implicated in linking obesity to cardiometabolic disease.1 Mechanistically, this has been
attributed to unique characteristics of VAT, most notably its propensity to become more
inflammatory2 and to activate obesity related stress-sensing pathways,3 releasing its secretory
products to the portal vein.4 Yet, it remains controversial whether particular lifestyle intervention
strategies can specifically decrease VAT beyond weight loss per-se,5-18 and whether diminishing
VAT is the prime essential mediator of the beneficial cardiometabolic effects of lifestyle
interventions. Physical activity (PA) has been shown to reduce VAT.15-17 In some studies, dietary
patterns exhibited no differential effect on specific abdominal fat depots in some studies,7, 8, 10, 13,
14
4
whereas other studies, in both humans and experimental animals, suggest that iintake
ntak
nt akee of ssimple
ak impl
im pe
carbohydrates,6, 12, 19 and trans-fatty acids, may specifically increase VAT, while mono- and
polyunsaturated fat decrease VAT accumulation.5, 9, 11
In addit
addition
itiionn to
it t VVAT,
AT,, in
AT increased
ncr
crea
ease
eased fa
se fat in thee liv
liver,
ver, pericardium,
peri
perica
ri card
cardiu
rd um, pancreas,
panc
pancre
r ass, ki
kkidney
dney
dn ey orr sk
skel
skeletal
e et
el etal
a
muscle
musc
scle may also
sc als
lsoo be re
related
elaated too adverse ca
cardiome
cardiometabolic
m tabo
me omes,20-22 ppossibly
boliic outcomes,
outtcom
ou ossi
sibl
sib y via me
mech
mechanisms
hanisms
ms
beyond elevated bo
bbody
d mass index (B
dy ((BMI).
MI).
) A few studies suggest tha
that
h t liver fat accumula
accumulation
l tion may
be more strongly associated than VAT with obesity’s metabolic complications23 including the
deterioration of glucose tolerance,24 possibly mediating the link between obesity and metabolic
dysfunction.25, 26 Similarly, accumulation of pericardial fat, particularly intra-pericardial fat, was
linked with the severity of coronary atherosclerosis.27 In contrast, increased superficial
subcutaneous adipose tissue (superficial-SAT) has been associated with improved
cardiometabolic risk markers, suggesting that it may be a protective, or a neutral, fat depot, as
previously reported.28 Yet it is unclear whether lifestyle interventions can differentially induce
long-term losses of various fat depots (i.e.: abdominal, pericardial and renal-sinus) or deposits
4
(i.e.: hepatic, intermuscular and pancreatic) with different cardiometabolic properties.29, 30, 31, 32 It
is also unclear whether defined clinical outcomes of such interventions can be directly attributed
to losses of distinct fat depots, beyond reduction in total body weight.18
In our previous two-year dietary randomized controlled trial (the DIRECT)33 and its four-
year follow-up,34 we found that Mediterranean and low-carbohydrate diets were effective in
improving cardiometabolic state and in reversing carotid atherosclerosis.35 Recently, the
PREDIMED study36 demonstrated reductions in cardiovascular events with Mediterranean diet.

In the current trial we aimed to test the hypothesis that, beyond long-term moderate weight loss,
it is possible to induce differential mobilization of VAT and other specific fat depots by different
lifestyle
ifestyle interventions, and to link the changes to specific clinical biomarkers.
Methods
Elig
gib
ibility and
Eligibility d Study
Stud
Stu y Design/Data
Desi
Des gn
si n/D
/Dat
ataa So
at our
u ce
Source
Thee rrandomized
andomized
ed ccontrolled
ontrrolled tr
on trial
rial (RCT)) ddesignated
esignnatedd ''CENTRAL'
CEN
ENTR
ENTRAL
TR AL' wa
was conducted
co
onduc
ucted between
uc betw
tweeen Octo
tw October
ober
2012 and April 20144 inn an isolatedd research center workplace in Israel wit
with
i h a monitoredd provid
provided
i ed
lunch. Recruitment was between May 2012 to September 2012, and from 346 volunteers, 278
subjects (Figure 1) meet the inclusion criteria. Abdominal obesity was the main inclusion
criteria [waist circumference (WC) >102cm for men and >88cm for women]; or dyslipidemia
[serum triglycerides (TG)>150mg/dL and high-density-lipoprotein cholesterol (HDL-c)
<40mg/dL for men and <50mg/dL for women]. Exclusion criteria were: serum creatinine
t2mg/dl; impaired liver function (tthreefold the upper level of ALT and AST), active cancer,
pregnancy or lactation, being physically active (>3h/week) or unable to take part in PA, or
participation in another trial. The study protocol was approved by the Medical Ethics Board and
5
the Helsinki Committee of the Soroka University Medical Center and did not change after trial
commencement. All participants provided written informed consent and received no financial
compensation or gifts. The investigators were blinded to the intervention group identities. The
data might not be available in public domains due to this confidential workplace legal demands
and requirements of the Nuclear Research Center Negev at Dimona, Israel. However, data might
be available with personal research communication.
Randomization and Interventions

Participants were randomly assigned to one of two equal-caloric diets for the entire study period:
a low-fat (LF) diet (n=139) or a Mediterranean/low-carbohydrate (MED/LC) diet (n=139). After
6 months of dietary intervention, each diet group was further randomized into adde
dedd PA ggroups
added rooup
ups
LFPA+, MED/LCPA+) or no added PA groups (LFPA–

(LF A
, MED/LCPA–
A
) for the last 12 months of
intervention.
ntervention. The randomization was performed with an allocation ratio of 1:1 to the two
treatment
reaatm
ment grou
groups,
ups, wi
w
within
th
hin
n strata
str
tratta of baseline
baseli
ba line
n VAT
VA
AT area
arrea for
for tthe
hee first
first
st randomization,
ran
a do
andomi
m zaati
tion
on,, an
on aandd of address
add
ddre
ress
res
of re
residence
esidence (t
(to
to en
ens
ensure
suree simi
similar
ilar geogr
geographical
g ap
aphhical distance
diistan
nce ffrom
rom
ro m th
thee gy
gym)
ym)
m in th
the
he ssecond
econd rrandomization
ando
domizattioon
(in Participants
in blocks off two). Pa
P rticipants were randomizedd after all had been recruited, in one phase, after
their strata characteristics were defined. The participants were aware of their assigned
intervention (open-label). Study investigators assessing outcomes were blinded to the group
assignments.
Diet Intervention
Both diets aimed for a moderate, long-term, weight loss with restricted intake of trans-fats and
refined carbohydrates, and increased intake of vegetables. Lunch, typically the main meal in this
population, was adjust to the specific diet groups and was provided by the workplace cafeteria.
The 18-month dietary intervention included a 90-minute nutritional session in the workplace
6
with clinical dietitians every week during the first month, and every month thereafter, in equal
format between the two dietary groups.
For the LF diet, the aim was to limit total fat intake to 30% of calories, with up to 10% of
saturated fat, and no more than 300 mg of cholesterol per day, and to increase dietary fiber.
Participants were counseled to consume whole grains, vegetables, fruits, and legumes and to
limit their consumption of additional fats, sweets, and high-fat snacks.
The MED/LC diet combined the Mediterranean and low-carbohydrate diets described in
our previous weight loss trial.33 The diet restricted carbohydrate intake to less than 40 g/day in
the first two months (induction phase), and thereafter a gradual increase up to 70 g/day, and
increased
ncreased protein and fat intake, according to the MED diet. The MED/LC diet was
was ri
rich
ch iinn
vegetables and legumes and low in red meat, with poultry and fish replacing beef and lamb. This
group was also provided 28g of walnuts/day [160 Kcal/84% fat, mostly PUFA (omega-Į-
linolenic
inooleenic acid)]
)] sstarting
taart
r in
ng fr
from
o tthe
om h tthird
he hird
hi r m
month.
onth.
Physical
Phys
ysic
ys i al Activity
Activ
vit
ityy IIntervention
ntterrven
ntion
tii
Starting after the ffirst

irst 6 months off dietary intervention, participants who were randomized to
added PA received a free supervised gym membership for the following 12 months. The
intervention included monthly 60-minute educational workshops, and training group sessions at
the gym, directed by certified fitness instructors, who were blinded to the assigned diets. The
exercise program included three sessions/week of mostly aerobic training. In the first month
participants started with 20 minutes of aerobic training at 65% maximum heart rate and 10
minutes of resistance training. Exercise was gradually increased to 45 minutes of aerobic training
at 80% of maximum heart rate and 15 minutes of resistance training. The resistance training
increased from one set of weights with 60% of the maximum weight to two sets with 80% of the
7
maximum weight and included: leg extension, leg curl, elbow flexion, triceps extension, lateral
pull-down, lower back extension and bent leg sit-ups.
Magnetic Resonance Imaging
To assess body fat depots/deposits, we performed a 45-minute 3-Tesla MRI (Ingenia 3.0 T, Philips
Healthcare, Best, the Netherlands) scans at baseline and after 18 months. In a sub-set of 158
randomly selected participants, we performed MRI measurement after 6 months of intervention.
The scanner utilized a 3D modified DIXON (mDIXON) imaging technique without gaps (2mm
thickness and 2mm of spacing), fast-low-angle shot (FLASH) sequence with a multi-echo two-
excitation pulse sequence for phase-sensitive encoding of fat and water signals (TR,3.6ms;
TE1,1.19ms; TE2,2.3ms; FOV 520×440×80mm; 2×1.4×1mm voxel size). Four images

ima
maage
gess of tthe
he
phantoms were generated, including in-phase, out-phase, fat and water phase.20 A breath-hold
technique
echnique was used to avoid motion artifacts when the chest and abdomen were scanned. In all oof
the
he qu
quantificati
quantifications
tioons and
ti a d comparisons,
an comp
compar
mparis
arison
is ons,
on s observers
obs
bserverss wer
were
ere bl
blin
blinded
inde
indedd to ttime
de imee po
im point
oin
i t and
and gr
grou
group
o p tr
ou ttreatment.
eatm
eatmen
tm ent.
en
All fat
fa depots were
wer
ere asse
assessed
essed
d by
by one or tw
two
wo raters.
ratter
ers. The
Thee Inter-observer
Int
nteer-oobserrver and
an intra-observer
intra-obse
in s rv
serverr
>0.96
correlations were >0 d fat storage pools. To validate
0.996 (P<0.001)) for alll measured i ate our mDIXON
valid O
quantification of fat ratio, we tested five 14 mm diameter polystyrene test tubes filled with 0%,
25%, 50%, 75% and 100% of oil and observed a linear relation.
Abdominal fat depots: We quantified abdominal fat using the MATLAB-based semi-automatic
software.28 We drew a continuous line over the fascia superficialis to differentiate between the
deep-SAT and superficial-SAT, and calculated mean VAT, deep-SAT and superficial-SAT from
three axial slices: L5-S1, L4-L5 and L2-L3. Quantification of the fat mass regions included the
area of each fat type and its proportion (percentage) of the total area of all fat types. Hepatic fat
content: We quantified the percentage of hepatic fat using PRIDE software from Philips Medical
8
Systems. We calculated mean percentage from four 2D slices (3cm intervals divided into
quarters) by utilizing the region of interest (ROI) approach, which is based on measurements of
tissue densities (fat/fat+water) using the Fat Ratio Calculation.37 We divided each slice into
quarters, and chose ROIs in each of the four quarters in order to represent the entire liver. We
determined the mean percentage of fat for each slice and quarter, and then calculated the mean
percentage of fat in the liver as a whole. Pancreatic Fat: Pancreatic fat percentage
was calculated from fat-phase images, as was done in an 1H-MRS study,32 by taking the average
of three successive 2D slices, each including all pancreatic regions. The MRI method was
validated against 1H-MRS,21, 38 and readily distinguished pancreatic parenchymal tissue from
VAT.39 Renal Sinus Fat: Renal-sinus fat was analyzed using the semi-automaticc MA
MATL
MATLAB-
TLAB
TLAB-
AB
based software. We acquired the amount of Renal-sinus fat area (cm²) from the middle axial slice
of each kidney at the level of the 1st-2nd lumbar vertebra, by calculating the area of the kidney
by polygon.
polygon. As thee right
rig
ghtt kkidney
idne
idneyy sits
ne sits slightly
sliigh
g tly lower
lo
owe
w r than
than
n the
the left
lef
e t too accommodate
acc
ccom
ommo
oda
date
tee the
the
h liver,
liv
iv
ver
er,, we
defined
defi
fine
fi n d the slices
ne y 40 Femo
slicces accordingly.
acccor
ording
gly.
ly Femoral
mora
ral Intermuscular
Inteermus
uscu
ula
larr adipose
addiposee ttissue:
adip issu
ue: We
W quan
quantified
ntiified
ed femor
femoral
oral
Intermuscular
ntermuscular adipose tissue (femoral-IMAT
(femoral-IMAT)
T) by
b calculating area (c m2) of single axial slice fr
((cm ffrom
om
mid-thigh of the right leg, between the femoral head to medial and lateral condyle.41 Pericardial
fat - volumetric quantification: Due to its unique features, with highly variable anatomy and
movement, pericardial fat was quantified volumetrically. Scans were performed in a single-shot,
breath-holding sequence using cardiac gating by the VCG technique (Vector Cardiac gating,
Philips Medical Systems). Pericardial fat was analyzed from the level of the pulmonary trunk to
the level of the apex of the heart in axial view. Imaging reconstruction into slices resulted in an
analysis range of 8 to 13 centimeters in a series of 16-26 slices on average, of 5mm thickness
without gaps. Volumes were calculated by multiplying total measured fat area by slice thickness.
9
We drew a polygon over the pericardium to differentiate between the internal pericardial fat
(IPF), i.e. epicardial fat, and external pericardial fat (EPF), also called intrathoracic fat. Non-
pericardial fat was carefully excluded from analyses.27
Clinical measurements
Standard wall-mounted stadiometer was used to measured height (±0.1cm) baseline, and
monthly body weight (±0.1 kg) without shoes. WC (±0.1cm) was measured at baseline, after 6
and at 18 months with an anthropometric measuring tape. Two blood pressure (BP)
measurements were recorded after resting using an automatic BP monitor (Datascope Accutorr 4
[Datascope]). Fasting blood samples were taken at baseline and at 18 months, at 8:00AM, and
were stored at -80°C. Fasting plasma glucose (FPG) was measured by Roche GLUC
UC
C3
hexokinase method). Plasma insulin was measured with an enzyme immunometric assay
(hexokinase
Immulite automated analyzer, Diagnostic Products, coefficient of variation (CV)=2.5%]. Serum

[Immulite
otaal cholesterol
total cholesterol
ol (CV
CV=1
CV= .33%)
=1 % , hi
(CV=1.3%), high
gh-d
gh -densi
-d sity-lipop
o rootein ccholesterol
op
high-density-lipoprotein hole
ho lest
lesterrol
st ol ((HDL-c),
HDL-
HD L c)), lo
low
w-d
-densiity
y-
low-density-
ipoopr
protein (LDL)
lipoprotein (LDL
DL)) cholesterol,
DL chooleestero
rol, and trig
ro glyycerides
e (CV
es
triglycerides CV=2
=2.1%)
1%) w
(CV=2.1%) eree ddetermined
were eteerm
rmin
ined enzym
in ymaatiically w
ym
enzymatically ith
with
a Cobas 6000
0 automatic
i analyzer (R
((Roche).
oche). P lasma le
Plasma lleptin
ptin levels were assessed
d by ELISA
S
(Mediagnost, CV=2.4%). All biochemical analyses were performed at the laboratories of the
University of Leipzig, Germany.
Monitoring and Motivating
Adherence to the diet was assessed by monitoring attendance of the nutritional sessions, and was
quantified via a self-administered validated electronic 127 item food-frequency questionnaires
(FFQ) at baseline and after 6 and 18 months.42, 43 Adherence to the exercise intervention was
monitored during the monthly group meetings and also quantified by calculating the METs/week
using an electronic self-reported validated PA questionnaires at baseline and after 6 and 18
10
months.44 To motivate compliance, participants were given a detailed individual report
summarizing all their measurements after the completion of the trial. Participants who did not
attend nutritional sessions or who decreased their gym attendance, as tracked by the electronic
gym entry monitor, were contacted by telephone. Text messages were sent to update participants
and to motivate adherence to the diets on specific occasions (such as before and after holidays).
Symptoms, adverse effects, quality of life, and medication usage were measured at baseline and
after 6 and 18 month.33

Statistical Analysis
The overall outcome was the change in body fat distribution, and the main primary specific
endpoint was VAT, with a priori hypothesis that VAT could be differentially altered
alteere
redd by llifestyle
ifes
ifessty
tyle
intervention
ntervention strategies. Secondary outcomes were hepatic, abdominal subcutaneous fat sub-
depots, pericardial,
p ricardial, pancreatic, renal sinus and femoral intermuscular fats. We performed
pe
intention-to-treat
nteent
ntion-to-treeat aanalyses,
n ly
na ysees,
s inc
including
ncclu
l di
ding
ng all
ll 278 pparticipants,
artici
ar cipant
nts,
nt s, bby
y im
iimputing
puuti
t ng
n the
the
h missing
mis
issi
siing observations
obsserrva
vati
tiion
ons
for al
all adiposee ti
tissues
isssues for
fo 388 individuals
ls with m
missing
issi
sing
ngg data
dat
ataa at 118-months
8-m
month
hs by the mu
multiple
ultipplee
mputation technique,455 wherein the following predictors were used in the imputation model: age,
imputation age
gender, baseline weight/BMI and WC at 18 months. For missing data of body weight, we used
the last observation carried forward. Sample size was estimated based on findings from a
previous 14-week intervention study, in which 33 postmenopausal obese women (57yr, 92kg,
36% body fat) were randomized to one of three interventions: diet alone, exercise alone, and diet
and exercise group. We observed a significant relative change in VAT of 12.8% (P<0.05). Thus,
the minimum detectable effect after 18 months for the primary VAT between the intervention
groups was estimated as 3.57cm2, and for an alpha=5% and power=80%, 250 participants were
required (calculated using Winpepi software). For the cardiac sub-study, sample size calculations
11
were based on results of a previous 20-week study among 32 postmenopausal obese women (58
yr, 91 kg, 44% body fat), considering an alpha=5% and power=80%, with the conservative
assumption of a mean detectable pericardial-volume difference of 10cm3 between the time
intervals. . Results are presented as means ± SD unless otherwise stated. Analysis of variance
with a covariance (ANCOVA) test was used in order to assess adherence to the interventions
(attendance of the group sessions) and differences in changes of reported nutrient intakes
between the diet strategies. General linear models were used to compare the trajectories of body
weight and WC across the four intervention groups. Paired t-tests were used to test for significant
changes of body fat depots at 18-months compared to baseline for the entire group, and for
nutrient changes within group. We used multivariate two-way

two-way ANCOVA and compared
com
mpa
pare
redd type
re type ooff
diet and PA as fixed factors (2*2 factorial design) to test changes in specific fat depots, using
mean of differences and 95% CIs for each intervention group over time. We calculated changes
from
m bbaseline
aseline to 18-months
18-
8 mo
m nt
nths
h and
hs and compared
com
ompaare
r d changes
chan
a gees between
an betw
twee
tweenn gr
ee ggroups,
ouups
p , wh
while ad
adju
adjusting
just
justin
st ing for
in for baseline
base
baseli
sel ne
li
values.
valu
ues. To
To assess
asses
ess the
es th effect
ef ooff the comb
combination
binationn of ddiet
iett and
and PA,
PA general
geenerall llinear
innear model
models
e s we
el w
were
re usedd
FPA–
with LF A
as the reference. All models were adj
adjusted
d usted for age, sex, baseline abdominall obesi
obesity
ity
and 18-month weight change. Multivariate analysis adjusting for sex, age and weight change was
used to predict visceral fat loss according to increasing METs/week. The associations between
changes in abdominal sub-depots, intra-hepatic fat, and changes in levels of blood biomarkers
were tested using multivariate linear regression models, adjusted for age, sex, weight change,
intervention group and baseline abdominal fat status (for the abdominal fat models) or baseline
intra-hepatic fat (for the hepatic model). Potential interactions between diet and exercise were
assessed by the ANCOVA models. We further performed separate sensitivity analyses within the
strata of male gender, abdominal obesity and dyslipidemia. Differences in changes of fat depots
12
between genders were assessed by ANCOVA. Homeostasis-model-assessment-of insulin-
resistance (HOMA-IR) was calculated according to the following equation: insulin
(U/ml)×fasting glucose(mmol/liter) ÷22.5. Statistical analysis was performed with IBM SPSS
(version 23). All P-values were two-sided, and P<0.05 was considered statistically significant.
Results
Participants were on average 48y old (range: 28.8-69.4y), mostly overweight to mildly obese
(mean BMI=30.8±3.8kg/m2), 75% (n=209) had elevated WC; the majority (89%) were men,
reflecting the workplace population (Table 1). Participants had mean of 33% VAT as a fraction
of total abdominal fat and 10% intra-hepatic fat (53% were with >5%), similar across
accrooss the
the two
two
andomized diet groups (P>0.37). Compared to women, men had less Superficial-SAT (40% vs.
randomized
25%, p<0.001) and more VAT than women (23% vs. 35%, p<0.001). Only 19% of the
part
ticcipants wer
participants ere re
er
were regu
ula
larl
rlyy taking
rl
regularly taaki
king
ng medications
med
dic
icationss (lipid-lowering:
(lipi
pid-lo
owe
weri
ring
ri ng: 12%;
ng 122%;
% anti-hypertensives:
ant
n i-hhyp
yper
erte
ertens
ten iv
vess: 8%
8%;;
anti
i-pplatelet: 7%;
anti-platelet: 7% oral
or gglycemic-control:
lyceemic-contro
ol:: 3%; and
a d insulin
an in
nsuuli
linn treatment:
treaatm
tr men
nt: 1%).
1%)
%). The
Th channges iin
changes n
medication use were negligible during th

he trial, and
the d were similar between
b tween groups.
be
Overall, the retention rate (Figure 1) was 93.2% at 6 months and 86.3% at 18 months,
similar to our previous randomized controlled trials.33, 46 Baseline demographic and metabolic
profiles were similar between those who completed the trial and those who did not. Sensitivity
analyses, using only complete data, yielded results similar to the intention to treat analyses we
have presented. At baseline, both groups consumed similar amounts of fat, carbohydrates and
protein (Table 1). During the intervention, reported energy intake decreased similarly across the
diet groups after 6 months (-27.0%±28.6 LF; -25.8%±46.8 MED/LC, p=0.85) and 18 months (-
21.6%±25.8 LF; -26.2%±25.8 MED/LC, p=0.18), and were all significantly lower compared to
13
baseline (P<0.001,). By 18 months, the reported carbohydrate intake of the MED/LC group had
decreased more than that of the LF diet group [mean-of-difference=-18.2% (95%CI=-25.2 to -
11.2)], while total reported fat intake (both saturated and unsaturated) of the LF group had
decreased more than in the MED/LC group [mean-of-difference=-10.1% (95%CI=-19.0 to -1.3)]
(Table 2). For the MED/LC group, there was a significant decrease in the reported intake of
trans fats and a marked increase in the reported intake of nuts (P<0.05 for all, vs LF). As
compared to the LF, the MED/LC diet decreased the proportion of carbohydrate after 6 (-14%
vs. +8%, p<0.001) and 18 months (-9% vs. +8%, p<0.001). At baseline, the amount of exercise
per week was similar for the LF and MED/LC groups (P=0.37). However, during the
ntervention there was a substantial increase in activity for the PA+ groups as compared
intervention com
mpaare
redd wi
with
th tthe
h
he
PA– groups (19.0MET/week vs 2.1MET/week; 95%CI=4.36-29.5

95%CI=4.36-29.5)
I ) (Table 2). PA+/- groups
maintained similar adherence to their respective assigned diets (not shown).
All inte
intervention
erv
r en
ention
o aarms
on r s induced
rm indu
induce
du ced a mo
ce m
modest
dest
s bu
st but
ut sign
significant
gnif
gnific
ificcan
ant w
weight
eigh
eigh
g t lo
loss of ssimilar
im
mil
ilar m
magnitude
agni
agn tu
ni tude
d
across
acro
oss groups (range
(ra
r ng
nge of difference
diffe
ferrence at 18 month
fe months
hs co
compared
omp
par
ared
ed tto
o bbaseline:
aseeline: -2.8k
-2.8kg
kg to -3
-3.1kg),
3.11kg
kg), which
ch
55.8%
corresponded to a 5. 8% baseline
% decline in baselin total-body
l-bbody weight at 6 months
i e total hs andd 3.2%
month 2 at 18
months(Figure 2a). However, compared to the LF diet group, MED/LC induced a greater
decrease in WC (Figure 2b). Moreover, PA groups, when added to either dietary arm, further
prevented WC rebound during the regain phase (p<0.05). Overall, despite inducing indifferent
moderate weight loss at 18 months, MED/LCPA+ decreased WC twice as much as LFPA–
(-5.2cm±6.1 and 2.5cm±6.5, respectively, p<0.05) (Figure 2b). As compared to the LF diet,
MED/LC diet significantly decreased diastolic BP after 6 months (-0.9mmHg vs. -3.4mmHg,
p=0.040). After 18-month, the MED/LCPA+ group decreased diastolic BP more than the LFPA– (-
2.8mmHg vs. 1.3mmHg, p=0.014) and the LFPA+ groups (-2.8mmHg vs. 1.1mmHg, p=0.023). A
14
similar pattern, although not statistically significant, was observed for systolic blood pressure
(Supplemental figure 1).
Diverse Response of Adipose Tissues and Deposits to Different Lifestyle Interventions
We observed a marked range in the changes of the different fat depots/deposits between baseline
and after 6 and 18 months of intervention following moderate body weight loss (3.2%) (Figure
2c); after 18-month, the decrease in intra-hepatic fat (29%), VAT (22%) and Intra-pericardial fat
(11%) were higher than the magnitude of decline observed in pancreatic fat and femur
intermuscular fat which decreased by 1-2%. Compared to women, men decreased more intra-
hepatic fat (-5.4% vs. -31%, p=0.008) and deep-SAT (-17% vs. -26%, p= 0.005), while women
decreased more pancreatic fat (-4.6% vs. -0.5%, p=0.021), (Supplemental table 1).
1). We
Weig
Weight
ight
ight and
and
n
VAT loss, however, were similar (-1.5% vs. -3.3% and -18% vs. -22%, p>0.07; in women vs.
men, respe
respectively).
p ctively).
A+ ggroup
The PA roupp had
ro had a significant
sig
igni
nifi
ni fica
fi c nt greater
greateer effect
efffeect on
on VAT
VA area
arreaa lloss
osss [mean-of-difference=-
[m
mea
eann-o
-of-
f diff
f- ffferren
ence
ce=
ce =-
7cm2; 95%CI
6.67
6.67cm 95%C
CI (-14.8
(-114.8
.8 to -0
-0.45)]
0.4 he PA- ggroup
. 5)] than th
the ro
oup ((Table
Tabl
Tab e 33),
bl ), iindependent
ndepen
ende
deent of we
weight
eig
ight
ht loss. We
W
estimate that an increase of one MET/week

k dduring
urin
i g the intervention was related to 4% reducti
reduction
ion
of VAT (p=0.022). As compared to the LF diet, MED/LC diet had a greater effect on intra-
hepatic fat [mean-of-difference=-1.56% absolute units; 95%CI:(-2.89 to -0.25)], on intra-
pericardial fat [mean-of-difference=-17.7mL;95%CI:(-31.2 to -4.39)] and on pancreatic fat
[mean-of-difference=-0.59% absolute units; 95%CI: (-1.10 to -0.08)] (Table 3), independent of
weight loss. Similar trends were found in models that did not adjust for 18-month weight
changes (Supplemental table 2). The MED/LCPA+ combination group induced the greatest loss
on intra-hepatic, pancreatic and intra-pericardial fat. In contrast, renal sinus fat and femoral inter-
muscular fat were not affected differentially by diet or activity (P>0.26 across groups for both),
15
and their loss corresponded only to weight loss per-se (P<0.05). When testing the individual
changes of VAT related to body weight loss, similar slopes were found between the diet groups
and for the PA groups (Supplemental figure 2a and 2b). Sensitivity analyses within the stratum
of men only revealed similar patterns. We further tested the main effects within strata of
abdominal obesity and dyslipidemia (Supplemental table 3). Similar patterns were found in the
abdominal obesity group (n=209), though findings we not statistically significant except for the
intra-pericardial fat changes (p=0.019). No statistically significant differences were found within
the dyslipidemia group (n=72).
Representative images (Figure 3) of changes in human fat depots/deposits in response to
he two extreme interventions, LFPA- vs. MED/LCPA+, are shown for two pairs off m
the men,
en, ma
en matc
matched
tche
tched
he
on age, baseline weight, WC, VAT percentage, and 18-month total-body moderate weight loss.
ges illustrate the superior capacity of MED/LCPA+ to induce intra-hepatic (Figure 3a),
These images
imag
panc
ncrreatic (Figu
nc
pancreatic guree 3b
gu
(Figure b) an
3b) andd pericardial
peri
perica
ri card
ca rdial fat
rd f t (Figu
fa g ree 3c)
gu
(Figure 3c)) lo r d to LFPA
oss ccompared
loss o paare
om PA-
A-
despite
desp
despitee si
sp similar
imi
m la
larr
weight
weig
ight
igh loss ind
induced
duced byy the tw
two lifestyl
lifestyle
y e interv
interventions.
ven
ntiions.
s.
Impact
mpact of Changes
Changes in Specific Fat-depot/de
Fat-depot/deposits Markers
d posits on Marke Cardio-Metabolic
k rs off Cardio-Metabollic Risk
Overall, after 18 months, the TG/HDL ratio decreased by 8.1%, HOMA-IR by 10.4% and leptin
by 20.9%. While physical activity did not have a differential effect on these biomarkers, the
MED/LC diet had a more favorable effect on lipids, as compared with changes in the LF group
(Supplemental table 4). MED/LC diet exhibited greater reductions in triglycerides (-
10.8mg/dl±28.0 vs -3.4mg/dl±43.8; P=0.040), TG/HDL ratio (-0.22±0.5 vs -0.15±0.47; p=0.023)
and an increase in HDL-c (+5.7mg/dl±7.1 vs +3.4mg/dl±7.5; P=0.009). No significant changes
over time and between intervention groups were found for HbA1c%, glucose, or CRP measures.
16
We next addressed the associations of reduction of specific fat depots with those cardio-
metabolic health biomarkers that were changed over the intervention. After adjustment for age,
sex and weight changes, VAT and intra-hepatic fat reduction were independently associated with
an improved lipid profile. Deep-SAT loss was specifically associated with improved insulin
sensitivity (decreased HOMA-IR), while superficial-SAT loss was specifically associated with
decreased leptin. (P<0.05; Figure 4). Sensitivity analyses, using only complete data, yielded
results similar to the intention to treat analyses we have presented.

Discussion
Our findings suggest that a Mediterranean diet, rich in unsaturated fats and low inn ca
carb
rboh
rb ohyd
oh ydra
ydrattes,
ra
carbohydrates,
and being physically active can improve cardiometabolic risk variables through changes in
visceral/ectopic fat depots that are not reflected by mild body weight changes alone. Moreover,
the
he va
various fatt ddepots
epo
pots eexhibited
po xhib
xh i itted hhighly
ib ighl
igh y diverse
d versee re
di rresponsiveness
sponsi
sp s ve
si vene
ness
nes to
ss to the
th
he interventions.
in
nte
terven
enti
ention
ti ons.
on s Wee identified
s. ide
dent
ntif
nt ified
if
two
woo ddistinct
istinct pa
patterns:
attern
att rns: ‘d
‘differentially
differrentially
y responsive
ressponsivee depots’
deepo
p tss’ that
that were
were sensitive
sensittivee to
to the type
typ
ype of
yp of
intervention,
ntervention, and ‘uniformly
‘ nifo
‘u ddepots’,
f rmly responsive de pots’, which
’ whi corresponded
d d only to weight lloss
h ch corresponde oss per-se,
irrespective of the intervention. Further, different fat depots were differentially related to various
cardiometabolic markers: VAT and intra-hepatic fat losses were uniquely associated with an
improved lipid profile, deep-SAT loss with improved insulin sensitivity, and superficial-SAT
loss remained neutral expect of association with decreased leptin.
Our study has several potential limitations. Total lean body mass or fat mass
measurements were not available from our MRI analysis. In addition, since we compared dietary
patterns, we cannot identify exact components responsible for the dietary effects, or to address
specific effects of aerobic versus resistance exercise. We relied on self-reported dietary intake,
17
although we did validate the dietary assessment tools.47 Self-reported diet assessments are
limited, as the energy intake changes are likely to be inconsistent with the body weight
measurements, as previously demonstrated using data from the DIRECT study.33 In addition, our
assessment of exercise intensity and cardiorespiratory fitness was limited, although electronic
gym entry records enabled us to further verify adherence, and the level of PA was ascertained in
the supervised sessions. The small number of women, reflecting the workplace gender
distribution, limits the generalizability of the results to women. Finally, one might argue that the
unique nature of the workplace in this study, which permitted a closely monitored dietary
intervention for a long-term period, makes it difficult to generalize the results to other free-living
populations. However, we believe that similar strategies to maintain adherence cou

ould
ld be
could be ap
appl
plie
pl ied
ie
applied
inn other workplaces, and may therefore be relevant for the general population. The strengths of
he studyy include the use of the 3-Tesla MRI measurements (considered the gold standard tool
the
for th
he quantifi
the ficcatiion
fi
quantificationo of
of sp
spec
ecif
ific
ific fa
specific fatt depo
pots) to quantify
depots) quaantifyy several
seve
severa
veral fa
ra at st
fat stor
orag
age si
storage ite
tes,
s,, aand
sites, n the
nd he hhigh
igh
igh
degr
grree of adhe
degree ere
rencee to
adherence o the iinterventions.
nterventions
ns.
O r fi
Ou
Our ffindings
ndings support the clinical
cli
l nical significance of sustained moderate weight loss on
reductions in cardiometabolic risk factors, and suggest that distinct lifestyle protocols may
uniquely induce loss of fat from specific anatomical sites.48 As shown in the DIRECT33, 34 and
PREDIMED36 studies, a Mediterranean diet appears to be superior to a low fat diet to improve
cardiometabolic health, even holding weight change constant. In the current CENTRAL trial,
while the MED/LC and LF diets achieved similar moderate weight loss by design, the MED/LC
diet resulted in a greater reductions of WC, triglycerides, and TG/HDL-c ratio and a greater
increase in HDL-c,33 which correspond to a greater decline in overall CV risk. Importantly, this
difference remained significant even after accounting for weight loss, suggesting an added, and
18
distinctive, value of the MED/LC and activity beyond the induction of weight change per-se. The
additive effect of PA on VAT reduction could be explained by a decrease in fatty acid storage or
an increased sympathetic tone, thereby activating lipolysis.49 A recent study found that a
carbohydrate-restricted diet increased net fat oxidation, but cutting an equal amount of calories
by restricting dietary fat intake had no such effect.50
Our study and other trials36 suggest that beyond the ability of moderate weight reduction
to decrease pericardial fat, a MED/LC diet in combination with exercise may be more effective
than LF diet in inducing such changes. Pancreatic fat was also differentially affected by our
interventions, but the functional significance of this finding is unclear. In our study, pancreatic
fat was the least dynamic fat depot. Although lipid deposition in the pancreas mayy be associated
ass
ssoc
o ia
ociate
ted
te
with impaired insulin secretion, dysglycemia and beta-cell dysfunction,32 this association has not
been a consistent observation. We found significant differences between diets for changes of
intra-hepatic
ntrra-hepatic fa
fat
fat,
t, ssuggesting
u ge
ug gest
sttin
ingg th
that
hat iintra-hepatic
ntra
nt r -he
hepatic fa
fat, m
may
ay
y play
pla
layy a particular
paart
rticcul
u ar rolee in mediating
med
e iati
t ng the
ti the
greater
grea
ate
t r benefici
beneficial
cial
a effects
efffeectts off M
MED/LC
ED/LC ccompared
ompareed to
o th
the
he LF ddietary
i tary
ie y iintervention.
nterrvent
ntiion.
nt
conclusion,
i n, this study demonstrates tha
IIn conclusio that iimproving
h t im proving nutritional
i ionall quality
nutrit quallity and be
bbeing
ing
physically active can improve cardiometabolic risk markers through changes in visceral /ectopic
fat depots that are not reflected by changes in body weight alone.
Author List
Yftach Gepner, PhD1*; Ilan Shelef, MD2*; Dan Schwarzfuchs, MD2*; Hila Zelicha, RD, MPH1;
Lilac Tene, MSc1; Anat Yaskolka Meir, RD, MPH1; Gal Tsaban, MD1,2; Noa Cohen, RD, MPH1;
Nitzan Bril, RD, MPH1; Michal Rein, RD, MPH1; Dana Serfaty, RD, MPH1;
Shira Kenigsbuch, RD, MPH1; Oded Komy, RD, MPH1; Arik Wolak, MD3;
19
Yoash Chassidim, PhD2; Rachel Golan, RD, PHD1; Hila Avni-Hassid, MD1; Avital Bilitzky, MD1;
Benjamin Sarusi, MSc4; Eyal Goshen, BA4; Elad Shemesh, MD1; Yaakov Henkin, MD2;
Michael Stumvoll, MD5; Matthias Blüher, MD5; Joachim Thiery, MD5; Uta Ceglarek, PhD5;
Assaf Rudich, MD, PHD1; Meir J. Stampfer, MD, DrPH6**; Iris Shai, RD, PHD1**
*Equal Contribution
**Corresponding authors
Affiliations
1
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2Soroka
University Medical Center, Beer-Sheva, Israel; 3Cardiac Imaging Unit, Department

Departmeentt ooff
Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel; 4Nuclear Research Center-Negev,
Dimona, Israel; 5Department of Medicine, University of Leipzig, Germany; 6Channing Division
of N
Network
etwork M
Medicine,
ediccin
ed ne,, D
Department
epar
epartm
tmen
tm entt of
en o Medicine,
Medicin
ne,
e BBrigham
righ
ham aand
nd Women’s
Wom
omen
e ’ss Hospital
Hos
ospi
os p ta
pi tall and
a d Harvard
an Harv
Harvar
rv ardd
ar
Medical
Me
edi
dical School
ol and
nd Harvard
Harvard
rd T.H. Chan
an Schoo
School
ol off Public
Pub
ubli
licc Health,
li Heaalth,, B
He Boston,
ostton
on, MA
MA
Sources of Funding
This work was supported by grants from: The Deutsche Forschungsgemeinschaft (DFG):
SFB1052; the Deutsche Forschungsgemeinschaft, Obesity Mechanisms (SFB 1052, A01 to MS,
B01 to MB, and B08 to IS), The Israel Science Foundation (ISF), Israel Ministry of Science and
Technology (grant # 3-13604), and the Dr. Robert C. and Veronica Atkins Research Foundation.
The foundations were not involved in any stage of the design, conduct, or analysis of the study
and had no access to the study results before publication. Authors have no conflict of interest to
disclosures. All authors had full access to all the data in the study and take responsibility for the
20
integrity of the data and the accuracy of the data analysis. The investigators were responsible for
the design and conduct of the study; collection, management, analysis, and interpretation of the
data; preparation, review, and approval of the manuscript; and decision to submit the manuscript
for publication.
Author Contributions
I.S, A.R, I.SI.S, M.J.S and D.S conceived the project. Y.G, I.S, D.S, H.Z, L.T, A.Y.M, N.C, N.B,
M.R, D.S, S.K, O.K, A.W, Y.H, R.G, B.S, E.G, E.S, Y.H, A.R and I.S designed the trial. Y.G,
H.Z, L.T, A.Y.M, G.T. N.C, S.K, O.K, H.A and A.B analyzed MRI scans. Y.G, Y.C, B.S, U.C,
M.S, M.B, J.T and I.S analyzed the data. A.R, Y.H, M.B and M.J.S supervised experiments.
exp
xper
erim
erim
men
ents
ts..
ts
Y.G, A.R, M.J.S and I.S wrote the paper. All authors discussed the results and commented on the
manuscript
p.
manuscript.
Disc
scllosures
sc
Disclosures
None
21
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25
Table 1. Baseline Characteristics of the CENTRAL Study Population, n=278
Diet groups
Low-fat diet Mediterranean/ low- All
n = 139 carbohydrate diet n = 278
n = 139
Age, y 48.4±9.2 47.4±9.3 47.8±9.3
Male (% of study population) 87.7 89.9 88.8
Body mass index, kg/m2 30.8±3.7 30.9±4.0 30.8±3.8
Waist circumference, cm
Men 107.1±8.7 108.1±9.0 107.6±8.8 *
Women 99.6±8.9 98.7±15.6 99.2±12.2
Blood pressure, mm Hg
Systolic 123.8±14.8 124.7±17.2 124.3±16.0
Diastolic 78.7±10.3 81.3±11.0 80.0±10.7

Number of positive metabolic syndrome criteria 2.2±1.1 2.1±1.2 2.2±1.1
Abdominal adipose tissue, area (cm2)
Total abdominal adipose tissue 534.4±150.5 534.2±154.2 534.3±152.1
Visceral
ceral adipose tissue 178.9±66.8 171.8±64.1 175.4±66.4
Deep p SAT 212.8±66.8 220.0±79.5 216.
21
216.4±74.3
6 4±
6. 4±74
74.3
74
Superficial
erficial SAT 142.6±62.2 142.4±64.0 14
142.5±63.0
42.
2 5±
5±63
63.0
63 .0
0
Proportion,
ortion, %
Visceral
ceral adipose tissue 33.8±9.2 32.8±10.6 33.3±9.9
Men
en 35.0±8.7 34.3±10 34.7±9.4 *
Women
omenn 25.1±7.9
255.11±7.9 19.3±5.8
19.3±5
19 5.8
8 22.5±7.5
Deep p SAT
SAT 39
39.7±5.9
9.77±5.99 40
40.7±6.1
.7±6
7±6.1
. 40.2±6.0
4 .2
40 2±6
±6.0
.0
Men
en 40.1±5.7
400.11±5
5.77 41.1±6.2
41.1±6
41 6.2
2 40.6±5.9
400.6±5.9
6 9*
Women
ommen 36.9±7.2
366.99±7
7.22 38.1±4.9
38.1±4
38 4.9
9 37.4±6.2
37 2
Superficial
erfic
iccia
iall SAT 26.5±7.6
266.55±7..6 26.5±7
26
26.5±7.8
7.8
8 26.5±7.6
26 6
Men
en 24.9±6.1
244.99±6
6.1 24.6±5.6
24.6±5
24 ±5.6
6 24.8±5.9
24.8±5
8±5.9
9*
Women
omen 38.1±7.2
38 1±7 2 42.6±5.7
42 6±5 7 40.1±6.9
40 1±6 9
Intra-hepatic fat, % 10.1±9.7 10.3±11.0 10.2±10.4
Pancreatic fat, % 17.3±4.7 17.5±5.5 17.4±5.1
Renal sinus fat, cm2 2.81±1.4 2.56±1.3 2.6±1.4
Femur IMAT, cm2 10.2±5.1 8.9±3.9 9.6±4.6
Pericardial fat volume (sub-study) (n = 40) (n = 40) (n = 80)
Intra-pericardial fat, mL 165.6±56.0 179.3±50.3 172.4±53.3
Extra-pericardial fat, mL 196.1±69.2 193.7±74.5 194.9±71.5
Blood biomarkers
Total Cholesterol, mg/dl 205.2±38.8 198.5±38.2 201.8±38.6
Serum HDL cholesterol, mg/dl
Men 41.5±11.2 41.8±8.7 41.6±10.0*
Women 55.4±17.8 53.9±15.0 54.8±16.4
Serum LDL cholesterol, mg/dl 123.8±31.9 120.8±30.9 122.3±31.4
Serum triglycerides, mg/dl 75.1±42.8 70.2±39.5 72.6±41.1
Ratio of triglycerides to HDL cholesterol 2.05±1.7 1.86±1.6 1.95±1.6
Ratio of total cholesterol to HDL cholesterol 5.13±1.8 4.86±1.5 4.99±1.7
26
HOMA-IR 4.54±3.0 4.62±3.3 4.58±3.2

HbA1c, % 5.53±0.5 5.56±0.5 5.54±0.5
Glucose, mg/dl 106.5±17.5 108.1±20.9 107.3±19.3
CRP, mg/liter 3.78±5.1 3.26±2.7 3.52±4.1
Leptin, ng/mL
Men 11.5±6.9 12.4±8.5 11.9±7.8 *
Women 35.6±21.2 33.1±22.7 34.4±21.6
Reported dietary intake
Carbohydrates, % 45.1±8.2 45.8±7.0 45.4±7.6
Total fat, % 34.8±4.8 34.2±4.6 34.5±4.7
Protein, % 20.1±3.9 20.0±3.6 20.1±3.7
Abbreviations: SAT, subcutaneous adipose tissue; IMAT, intermuscular adipose tissue. Values in the Table are
means ± standard deviation. * P < 0.01 between gender groups using an independent t-test. The macronutrients
are percentages of total reported energy intake, based on self-reported food-frequency questionnaires (FFQ).
CRP- Plasma high-sensitivity C-reactive protein.
27
Table 2. Changes in Reported Dietary Intake and Physical Activity during 18 Months of
Intervention between the Intervention Groups
Mediterranean/ P value
Low-fat/low-kcal low-carbohydrate between
Variable diet (n = 139) diet (n = 139) groups
Energy change from baseline (kcal/day) -729.9±947.2* -869.9±932.6* 0.27
% change from baseline -21.6±25.8 -26.2±25.8 0.18
Total carbohydrates
% of energy at baseline 45.2±8.2 46.2±7.0 0.27
% of change in g/d from baseline -21.3±28.4 -39.5±24.3 <0.001
Absolute change from baseline (g/d) -85.8±118.9* -143.1±121.1* <0.001
Total fat
% of change in g/day from baseline -21.0±27.8 -11.5±37.2 0.033

Absolute change from baseline (g/d) -28.2±41.3* -20.0±41.7* 0.14
Protein
% of change in g/d from baseline -16.0±32.2 -14.8±32.8 0.79
Absolute
bsolute change from baseline (g/d) -32.8±56.5* -29.7±53.2* 00.68
0. 68
Monounsaturated
nounsaturated fat
% of change in g/d from baseline -19.3±29.2* -7.3±41.4* 0.014
Polyunsaturated
yunsaturated fat
% of change in g/d from baseline -19.5±26.8* -12.0±38.1* 0.092
Saturated
urateed fat
fat
% of change
change in g/d /d from
fro
ro
om baseline
base
ba seeli
l ne
n -21.8±31.2*
-21
21.8±3
21 ±31.2* -12.3±40.5*
-12
12.3
3±4
± 0.5*
5 0.052
0..05
0522
Trans
ns fat
f t
fa
% off change
change in g/d /d from
frromm baseline
ba ne
% change
chan
ange
an ge from baseline
basseliine
ba -14.9±45.8*
-14
1 .9±4
14 ±45.8*
8* -22.6±40.6*
-22.6
6±40.
0.6*
0. 6
6* 0.029
0.029
Dietary
tar
aryy cholesterol
chhol
o esteero
r l
% of change in g/d from baseline -19.4±38.3*
19 4±38 3* -10.7±57.8*
10 7±57 8* 0.19
0 19
% change from baseline -6.2±36.3* -18.7±32.8* 0.008
Nuts
% of change in g/d from baseline 38.7±216 214.2±476 0.002
Physical activity randomization Non-exercise group Exercise group
(n = 130) (n = 126)
Baseline metabolic equivalent of task
(MET)/week 37.7±32.2 34.5±27.0 0.37
Change in MET/week (after PA randomization)
from 7 months to 18 months 2.1±38.3 19.0±33.8 0.009
*
P < 0.05 for within group test compared to baseline of absolute changes using paired t-test. Changes in reported
energy intake, total carbohydrates, fats and protein intake were similar between PA randomized groups. Values
in the Table are means ± standard deviation.
28
Table 3. Effect of Diet with or without Physical Activity on MRI- assessed Fat Depots over 18 Months of Intervention
2u2 factorial analysis

Low-fat diet MED/Low-carb diet MED/low-carb vs. low-fat PA+ vs. PA-
All Differences of the Differences of the
18-month changes (delta) PA– (Ref) PA+ PA– PA+ (n = 278) mean (95% CI) P-value mean (95% CI) P-value
Primary outcome
Visceral adipose tissue cm2 -32.9±33.5 -48.9±43.0† -31.1±32.7 -47.3±36.6* -39.5±37.1|| -0.58 (-8.15 to 6.99) 0.88 -6.67 (-14.8 to -0.45) 0.037
Secondary outcomes
Intra-hepatic fat %, absolute units -3.72±7.12 -3.88±6.32 -3.67±6.51 -4.74±7.63 -3.99±6.90|| -1.56 (-2.89 to -0.25) 0.020 0.19 (-1.15 to 1.53) 0.28
Pancreatic fat %, absolute units 0.12±1.65 -0.10±2.27 *
-0.40±2.32 -0.69±2.42 -0.26±2.18 ‡ -0.59 (-1.10 to -0.08) 0.02 0.023
2 3 -0.13 (
(-0.88
-0.88 to 0.63) 0.74
# 3
Intra-pericardial fat cm -10.1±27.8 -15.9±25.0 -15.7±20.5 -37.2±27.1 -18.9±26.7 -17.7 (-31.2 to -4.39) 0.
* || 0.009
0.0009 --2.45
2.45
2. 455 ((-15.6
-15
1 .6 to 10.7) 0.71
Extra-pericardial# cm3 -25.7±30.2 -23.4±29.5 -37.5±28.2 -34.4±34.0 -29.7±30.4 || -1.02 (-15.1 to 13.1) 0.88
888 6.38
6. 38 (
(-7.61
-7
7. 61 ttoo 220.4) 0.90
2
Superficial SAT cm -21.3±29.1 -32.6±27.3 -23.4±27.5 -27.2±22.4 -25.8±27.0|| 0.02 (-6.12 to 6.15) 0.99 -1.79 (-8.24 to 4.66) 0.59
2
Deep SAT cm -44.7±46.2 -66.7±37.4 -51.3±44.4 -64.7±45.0 -56.2±44.3 -6.03 (-14.5 to 2.43) 0.16
|| 0.81 (-7.78 to 9.41) 9 0.85
Renal sinus fat cm2 -0.18±0.49 -0.20±0.50 -0.21±0.04 -0.20±0.04 -0.20±0.44 || -0.95 (-0.26 to 0.08) 0.27 0.11 (-0.08 to 2.92)
2 0.26
2
Femur IMAT cm -0.19±2.11 -0.81±2.74 -0.43±1.95 -0.12 12±2.27 -0.37±2.27 0.31 (-0.32 to 0.94)
-0.12±2.27
12 || 0.33 -0.01 (-0.68 to 0.69) 0.99
Values in the tablee are mean
m
means
ean
ans ± SD
SD.
D. Ab
Abbr
Abbreviations:
b evia iati
tions: MED, Mediterranean; SAT, subcutaneouss aadipose dipose tissue; IMAT, in intermuscular
ntermusscu cular adipose tissue. The Table represen represents the crude,
unadjusted numbers ers off the
th
he changes from
omm baseline.
baselelin
el i e. Th
The st stat
statistical
atisticaal an
at anal
analysis
alys
al ysis was
ys as pperformed
erformed d bbyy multivariate
multivariaate ggeneral
mu ener
en e al lin
linear
ineaeaar reregr
regression
gressi sion
o models
model elss for
el fo
or all fat de
ddepots
p ts and
po and ectopic
ectopic fat that were
adjusted for age, sex, bbaseline
aseline abdominal obe obesity
esiity ((for
for
orr tthe
he aabdominal
bddom
omiinall ffat
a ddepots)
at epootss) or intra-hepatic
intra--heepattic fat (for
(for the
the intra-hepatic
int
ntraa-hepa
paticc fat)fatt) aand
ndd 18 mo mont
months
nth
nt hs w
weight
eigh
eight ch
gh ges. * p<
changes.
hannge p<0.05
p<0.0.05 for
f mean of
differences and 95%5% CIsCIIs MED/LCPA+ vs. LF
C FPA
PA–
A–
group.
grou
ouup. †: p<0.08
p< <0.
0 08 for mean
meeann of differences
differences aandnd 9595% CI LFPA+ v
5% CIs s. LFPA
vs. PA-
A- ‡
. P < 00.05, 05, ||| P < 0.01 forr changes
.0 chan
ch ngees at 18-m
18-months
months compared to
mon
baseline by paired d t-te
t-test
estt for the entire gr ouup. # P
grou
group. Pericardial
erica
cardial fatfaat sub-study
sub-study (n=80
(n=80)0) was adjus
adjusted
steed fo
for
or 18-mo
18-month
mont
mo nth
nt h we
weig
weight
ightt chang
ig changes.
nges. Inten
Intention-to-treat
ntionn-tto-treat anal
analyses,
lysses,, in
including
ncluding aall ll 278 participants by
multiple imputationon (M
(MI)
MI)) technique. AfAfter
fteer 188 mmonth
ontth of interv
intervention,
rveention, 38 pparticipants
rv a tiicip
ar pants drop
dropped
opp
op ped ooututt an
and
nd hhad
ad incomp
incomplete
mplete ssets etts of ob
observations.
bseervaatiion
o s. The following
fo
ollo
l wiing g 86.3% pparticipants
arrticip completed
the intervention: LFPA- (n = 558), FPA+
8), LF A+
(n = 660),
0)), M
MED/LC
ED D/LCPA PA-
A-
(n = 56)) and
and MED/LC
MED ED/L
ED / CPA+ (n = 66 66).
6).
29
Figure Legends
Figure 1. Flow chart of the CENTRAL study
Figure 2. Dynamics of weight, waist circumference and human fat depots/deposits during
18 months of intervention
(a) 18-m trajectory (mean ± SE) of body weight across diet and physical activity intervention
groups (n=278). (b) Waist circumference changes (mean ± SE) after 6 and 18-m across diet and
physical activity intervention groups (n=278). General linear models were used to compare
changes of body weight and waist circumference. Weight loss between diet groups
groupps after
afte
aft r6
te
months (p=0.19) * p < 0.05 for MED/LCPA+ and LFPA+ as compared to the LFPA-. (c) MRI
illustration
llustration of the human fat depots/deposits at baseline and after the 18-month interventions
foll
following
low
wing moderate
mode
dera
der te w
weight
eigh
ei ghtt loss
gh lo
oss (6%):
(6%
6%): (I)
(I)
I abdominal
abdom
o in
om nal fat-
fat
at- vi
at visc
visceral
scer
sce al ffat
a (gr
at (green),
gree
e n)
n), de
deep
ep SAT
A ((light
AT ligh
li ghtt
gh
blue
blue),
e), superficial
superfici
cial
a S
SAT
AT (blue),
(bluee),
) non-classified
non-classi
sified ffat
a (r
at (red),
redd),, pe
peri
peri-muscular
ri-mu
ri muscuulaar fa
fat
at (pu
(purple);
purple); ((II)
pu I ) in
II intra-
hepatic fat; ((III)cardiac

III)carddiac fat- of intra-pericardial
intra-pericarddial fat (IPF,
( PF, light blue)
(I b ue)) and a similar reduction off
bl
extra-pericardial fat (EPF, purple, n=80 for the cardiac substudy); (IV) pancreatic fat (red); (V)
renal sinus fat (blue); (VI) femur intramuscular fat (green).
Figure 3. MRI Illustrations. Differences in dynamic of fat depots between the extreme
intervention groups in two pairs of participants with similar baseline body weight and weight
loss. MRI scans of a selected pair of men aged 58y, with a waist circumference of 108 cm and
33% of visceral fat at baseline, who were randomized to LFPA– or MED/LCPA+ groups. Despite
the similar weight loss (-6.5%), they exhibited different reductions of intra-hepatic fat (IHF)
30
(Fig. 1a) and pancreatic fat (red) (Fig. 1b). Another example for a pair of men aged 52 y, with a
waist circumference of 107 cm and 37% visceral fat at baseline, and the same weight loss (-
5.5%) demonstrates a greater reduction of intra-pericardial fat (IPF, light blue) and a similar
reduction of extra-pericardial fat (EPF, purple) (Fig. 1c) for the man randomized to the
MED/LCPA+ group vs the man randomized to the LFPA– group.
Figure 4. Independent* associations between 18-month changes in abdominal fat depots,

intra-hepatic fat and biomarkers
*MV linear regression models, adjusted for age, sex, weight changes, the 4 intervention groups,
and for baseline abdominal obesity (for the abdominal fat depots) or intra-hepaticc fa
at (f
fat (for
o tthe
or he
ntra-hepatic fat). The amount and direction by which reduction in abdominal fat sub-depots and
intra-hepatic
p tic fat were associated with changes in biomarkers are UHSUHVHQWHGE\ȕVWDQGDUGL]HG

ntra-hepa
intra-hepatic
coef
e fi
efficient. P<
coefficient. < 00.05
.05
05 con
o si
on side
d reed as sstatistically
de
considered t tiist
ta stically
y ssignificant
igni
nificaant and
and values
vallue
uess ar
re give
are venn in bbold
ve
given oldd in
n tthe
he
ablle.
e Intention
table. n-to-ttreaat anal
Intention-to-treat lyses, includi
analyses, ing alll 278
including 2788 participants
paart
rtic
icip
icipan
nts byy mul
ltiiplle imputation
multiple imputaati
ationn (MI)
echnique. A
technique. fter 18 month of intervention, 38 participants dropped
After d out and had
had incomplete sets
of observations. The following participants completed the intervention: LFPA- (n = 58), LFPA+ (n
= 60), MED/LCPA- (n = 56) and MED/LCPA+ (n = 66). CRP- Plasma high-sensitivity C-reactive
protein.
31
Months Baseline 6 months 18 Months
a 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 b 0
0 -1
Waist Circumference (cm)

Low-fat PA-
Weight Changes (kg)

-1 Low-fat PA+ -2
-2 MED/Low-carb PA- -3
MED/Low-carb PA+ **
-3 -4
-4 -5
-5 -6
-6 -7
-7 -8
-8 -9
c I. Abdominal
bdominal fat II. Intra-Hepatic fat III. Cardiac fat IV. Pancreatic fat V. Renall Sinus ffatt
Sinus fa VI.
V Intramuscular fat
VI
21.4%
27.6%
Baseline 4.2cm2
13.9cm2
13
VAT 33%, DSATT 41%
41
1% , SSAT 26%
26% 132cm3 EPF%
IPF% 132 m3
% 118cm
11
18cm
17.6%
After 18m of 5.4%

%
intervention 3.2cm2
IPF% 86cm3 EPF% 63cm3 10.2cm2

10
VAT 26%, DSAT 44%
44% , SSAT 30
30%
%
a. Intraa hepatic fat % Pair I. Two males, age =58y, baseline VAT= 33% WC=108cm
Low
w Fat
at Diet MED/Low Carb
b Diet + PA
IHF= 24.1% IHF= 27.6%
Baseline
IHF== 15.
15.9%
.9% IIHF=
HF= 5.4%
5.4
4%
After 18m
weight loss=-6.5%
-8.2% units (-34%) -22.2% units (-80%)

b. Pancreaticc fat % Pair I. Two males, age =58y, baseline VAT= 33% WC=108cm
Low Fat
at Diet
w Fa
at Diiet MED/Low Carb
b Diet
Diiet + PA
PANCREATIC-F=23% PANCREATIC-F=21.4%
Baseline
PANC
CREATIC-FF=22.7%
PANCREATIC-F=22.7% PANCREATIC-F=17.6%
PAN
NCREATIC
C-F=17
7.6
6%
After 18m
weight loss=-6.5%
-0.3% units (-1.3%) -3.8% units (-17.8%)

c. pericardial fat, 3D Pair II. Two males, age= 52y, Baseline VAT= 37%, WC=107cm
Low
w Fat
at Diet MED/Low Carb
b Diet + PA
Baseline
IPF 241mL EPF 276mL IPFF 1

178mL
78mL EPF 204mL
After 18m
weight loss=
= -5
-5.5%
5.5%
IPF 224mL EPF 184mL IPF 122mL EPF 153mL

IPF EPF IPF EPF
-17mL (-7%) -52mL (-33%) -56mL (-31%) -51mL (-25%)
0.3 Δ Visceral fat Δ Deep-SAT Δ Superficial-SAT Δ Hepatic fat
0.2 *
0.1
β coefficient
-0.1
-0.2
*
* * *
-0.3
* * *
* *
-0.4
HDLL-c
HD
Δ HDL-c Trigglyyceri
ride
ri
Δ Triglyceride d TG/H
TG / DLL
/H
Δ TG/HDL C OL/H
CH /H
/HDL
H
Δ CHOL/HDL T taal
To
Δ Total ΔHbA1c
Δ Hb
bA1
1c Δ Glucose
G uccos
Gl oe Δ HOMA-IR
HO
OMA
M -IR Δ Leptin
Leept
ptin Δ CRP
Cho
Cholesterol
olesteerool
Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: The CENTRAL
MRI Randomized Controlled Trial
Yftach Gepner, Ilan Shelef, Dan Schwarzfuchs, Hila Zelicha, Lilac Tene, Anat Yaskolka Meir, Gal
Tsaban, Noa Cohen, Nitzan Bril, Michal Rein, Dana Serfaty, Shira Kenigsbuch, Oded Komy, Arik
Wolak, Yoash Chassidim, Rachel Golan, Hilla Avni-Hassid, Avital Bilitzky, Benjamin Sarusi, Eyal
Goshen, Elad Shemesh, Yaakov Henkin, Michael Stumvoll, Matthias Blüher, Joachim Thiery, Uta
Ceglarek, Assaf Rudich, Meir J. Stampfer and Iris Shai
Circulation. published online November 15, 2017;

Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2017 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2017/11/14/CIRCULATIONAHA.117.030501
Data Supplement (unedited) at:

http://circ.ahajournals.org/content/suppl/2017/11/14/CIRCULATIONAHA.117.030501.DC1
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SUPPLEMENTAL MATERIAL
1
Supplemental figure 1. Dynamics of systolic and diastolic blood pressure during 18 months
of intervention
18-months changes of systolic blood pressure (a) and diastolic blood pressure (b) across diet and
physical activity intervention groups (n=278). Lines represent mean changes ± SE. General linear
models were used to compare changes between groups. * P < 0.05 for MED/LCPA+ as compared to
LFPA- and LFPA- groups.
2
Supplemental table 1. Body fat mobilization over 18-months of intervention between
genders
Men, n=247 Women, n=31 P-value
18-month changes
(Relative change)
Visceral adipose tissue -22.4±19.05 -17.6±12.5 0.608
Intra-hepatic fat -31.6±48.1 -5.4±52.8 0.008
Pancreatic fat -0.5±12.8 -4.6±11.9 0.021
Intra-pericardial fat# -11.4±15.5 -5.0±13.7 0.425
Extra-pericardial# -16.5±15.4 -7.9±17.4 0.078
Superficial SAT -17.3±15.0 -14.6±12.4 0.477
Deep SAT -26.3±16.4 -17.1±12.9 0.005
Renal sinus fat -7.8±16.9 -6.5±14.8 0.443
Femur IMAT -1.8±0.4 0.4±18.8 0.385
Values in the table are mean relative change ± SD. ANCOVA test was used to compare between genders and was
adjusted for weight change.
3
Supplemental table 2. Effect of diet and physical activity on fat depots over 18 months of
intervention without body weight changes adjustment
MED/low-carb vs. low-fat PA+ vs. PA-
18-month changes (delta) P-value P-value
Visceral adipose tissue cm2 0.001 0.78
Intra-hepatic fat % 0.22 0.18
Pancreatic fat % 0.21 0.024
Intra-pericardial fat cm3 0.036 0.008

Extra-pericardial# cm3 0.19 0.89
Superficial SAT cm2 0.023 0.64
Deep SAT cm2 0.009 0.65

Renal sinus fat cm2 0.91 0.67
Femur IMAT cm2 0.86 0.47
Abbreviations: MED, Mediterranean; SAT, subcutaneous adipose tissue; IMAT, intermuscular adipose tissue. The
statistical analysis was performed by multivariate general linear regression models for all fat depots and ectopic
fat that were adjusted for age, sex, baseline abdominal obesity (for the abdominal fat depots) or intra-hepatic fat
(for the intra-hepatic fat). Intention-to-treat analyses, including all 278 participants by multiple imputation (MI)
technique. After 18 month of intervention, 38 participants dropped out and had incomplete sets of observations.
The following 86.3% participants completed the intervention: LFPA- (n = 58), LFPA+ (n = 60), MED/LCPA- (n = 56) and
MED/LCPA+ (n = 66).
4
Supplemental figure 2: Individual changes of visceral fat related to body weight across diet
and physical activity grou
5
The dots represent the individual changes of visceral fat over 18 months as compared to body weight change
across diet groups (a) and physical activity groups (b). Abbreviations: MED, Mediterranean; PA, physical activity
Supplemental table 3: Effect of diet and physical activity on MRI- assessed fat depots
stratify for abdominal obesity and dyslipidemia
22 factorial analysis

MED/low-carb vs. low-fat PA+ vs. PA-
18-month changes (delta) Differences of the mean P-value Differences of the P-value
(95% CI) mean (95% CI)
Abdominal obesity only, n=209
Visceral adipose tissue cm2 3.21 (-5.01 to 11.45) 0.42 -5.83 (-14.19 to 2.53) 0.17
Intra-hepatic fat % -0.14 (-0.35 to 0.80) 0.21 -0.13 (-0.35 to 0.09) 0.24
Pancreatic fat % -0.47 (-1.15 to 0.20) 0.17 -0.51 (-1.20 to 0.18) 0.15
Intra-pericardial fat# cm3 -16.69 (-30.45 to -2.94) 0.019 -10.59 (-24.21 to 3.03) 0.12
Extra-pericardial# cm3 2.89 (-12.84 to 18.63) 0.71 -1.13 (-16.71 to 14.45) 0.88
Superficial SAT cm2 1.11 (-5.29 to 7.51) 0.73 0.99 (-5.51 to 7.50) 0.76
Deep SAT cm2 -0.09 (-9.64 to 9.44) 0.98 3.81 (-5.88 to 13.51) 0.44
Renal sinus fat cm2 0.01 (-0.12 to 0.13) 0.95 0.01 (-0.12 to 0.14) 0.93
Femur IMAT cm2 0.16 (-0.55 to 0.89) 0.64 -0.12 (-0.85 to 0.62) 0.75
Dyslipidemia only, n=72
Visceral adipose tissue cm2 -0.10 (-14.75 to 14.55) 0.98 4.88 (-10.56 to 19.45) 0.55
Intra-hepatic fat % -0.25 (-0.63 to 0.13) 0.19 0.03 (-0.35 to 0.41) 0.87
Pancreatic fat % 0.26 (-1.08 to 1.60) 0.69 -0.39 (-1.75 to 0.97) 0.56
Superficial SAT cm2 -2.12 (-13.56 to 9.02) 0.70 5.06 (-6.34 to 16.47) 0.37
Deep SAT cm2 -12.59 (-30.11 to 4.92) 0.15 14.18 (-3.75 to 32.12) 0.12
Renal sinus fat cm2 -0.13 (-0.36 to 0.09) 0.26 0.10 (-0.13 to 0.34) 0.39
Femur IMAT cm2 0.03 (-1.25 to 1.30) 0.96 -0.01 (-1.32 to 1.29) 0.98
Abbreviations: MED, Mediterranean; PA, physical activity SAT, subcutaneous adipose tissue; IMAT, intermuscular
adipose tissue. The statistical analysis was performed by multivariate general linear regression models for all fat
depots and ectopic fat that were adjusted for age, sex, baseline abdominal obesity (for the abdominal fat depots)
or intra-hepatic fat (for the intra-hepatic fat). # n=62 for the pericardial sub-study.
6
Supplemental table 4. Effect of diet and physical activity on cardiometabolic biomarkers over 18 Months of Intervention
22 factorial analysis

Low-fat diet MED/Low-carb diet MED/low-carb vs. low-fat PA+ vs. PA-
All Differences of the P- Differences of the P-
18-month changes
(delta) PA– (Ref) PA+ PA– PA+ (n = 278) mean (95% CI) value mean (95% CI) value
HDL mg/dl 3.30±6.47 3.47±8.41 6.43±6.76 5.00±7.38 4.53±7.38 2.49 (0.65 to 4.34) 0.008 -0.38 (-2.26 to 1.51) 0.69
Triglyceride mg/dl -1.12±27.2 -5.53±54.9 -13.68±27.4 -8.45±28.4 -7.19±36.7 -0.11 (-0.20 to -0.01) 0.027 -0.09 (-0.11 to 0.09) 0.86
TG/HDL Ratio -0.20±0.44 -0.11±0.48 -0.22±0.37 -0.22±0.52 -0.19±0.46 -0.05 (-0.08 to -0.01) 0.026 0.02 (-0.03 to 0.05) 0.47
CHOL/HDL cm3 -0.18±1.02 -0.12±1.22 -0.56±1.07 -0.45±1.00 -0.33±1.09 -0.36 (-0.62 to -0.09) 0.009 0.03 (-0.23 to 0.31) 0.79
Total Cholesterol mg/dl 13.25±29.1 7.74±35.9 1.09±44.2 3.07±30.5 6.21±35.3 -7.94 (-17.1 to 1.30) 0.092 -1.59 (-11.0 to 7.83) 0.74
HbA1c % -0.01±0.36 -0.08±0.19 -0.05±0.39 -0.04±0.27 -0.05±0.31 -0.02 (-0.08 to 0.08) 0.96 -0.04 (-0.12 to 0.04) 0.33
Glucose mg/dl 2.53±15.7 -0.55±13.1 0.12±18.6 -0.61±15.7 0.34±15.83 -1.12 (-5.37 to 3.13) 0.60 -2.54 (-6.89 to 1.79) 0.25
HOMA-IR -0.90±1.84 -1.14±2.58 -1.13±3.17 -0.45±1.88 -0.90±2.41 0.20 (-0.13 to 0.82) 0.53 0.29 (-0.35 to 0.94) 0.36
Leptin ng/mL -4.9±9.80 -3.7±5.4 -4.9±12.0 -4.9±5.1 -4.6±8.4 -1.31 (-3.22 to 0.61) 0.18 -0.22 (-2.19 to 1.73) 0.82
CRP mg/liter -0.78±5.33 -0.58±4.60 -0.23±2.02 -0.17±2.77 -0.43±3.89 0.35 (-0.69 to 1.40) 0.50 0.19 (0.87 to 1.26) 0.71
Values in the table are means ± SD. Abbreviations: MED, Mediterranean; TG, Triglyceride; CRP- Plasma high-sensitivity C-reactive protein. The Table represents the crude, unadjusted
numbers of the changes from baseline. The statistical analysis for mean of the differences between diets and physical activity groups were performed by multivariate general linear
regression models for biomarkers that were adjusted for age, sex, baseline abdominal obesity and 18 months weight changes. Due to non-normal distribution, triglyceride was analyzed using
log transformation. Intention-to-treat analyses, including all 278 participants by multiple imputation (MI) technique. After 18 month of intervention, 38 participants dropped out and had
incomplete sets of observations. The following 86.3% participants completed the intervention: LF PA- (n = 58), LFPA+ (n = 60), MED/LCPA- (n = 56) and MED/LCPA+ (n = 66).
7
We thank the CENTRAL participants for their significant contribution. We thank California Walnut
Commission for kindly supplying the walnuts. We thank Osnat Tangi-Rosental1, Dr. Amir Tirosh1, Dr. Rafi
Gonen4, Dr. Lena Novak1, Dr. Lior Zeler2, Dr. Ilana Harman-Boehm2, Victor Haddad1, Roman Tsirkin2,
David Shushan2, Shula Witkow2, Liz Shabtay1, Julia Kovshan1, Hadar Cohen1, Dr. Omri Orr1 and Dr. Moti
Salti2 for their valuable contributions for this study.

Effect of Distinct Lifestyle Interventions On Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial

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Effect of Distinct Lifestyle Interventions On Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial

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10.1161/CIRCULATIONAHA.117.

Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools:

The CENTRAL MRI Randomized Controlled Trial

Yftach Gepner, PhD et al.

The full author list is available on page 19.

AddressHV for Correspondence:

implicated in linking obesity to cardiometabolic disease.1 Mechanistically, this has been

polyunsaturated fat decrease VAT accumulation.5, 9, 11

dysfunction.25, 26 Similarly, accumulation of pericardial fat, particularly intra-pericardial fat, was

linked with the severity of coronary atherosclerosis.27 In contrast, increased superficial

subcutaneous adipose tissue (superficial-SAT) has been associated with improved

to losses of distinct fat depots, beyond reduction in total body weight.18

improving cardiometabolic state and in reversing carotid atherosclerosis.35 Recently, the

PREDIMED study36 demonstrated reductions in cardiovascular events with Mediterranean diet.

[serum triglycerides (TG)>150mg/dL and high-density-lipoprotein cholesterol (HDL-c)

be available with personal research communication.

Randomization and Interventions

a low-fat (LF) diet (n=139) or a Mediterranean/low-carbohydrate (MED/LC) diet (n=139). After

LFPA+, MED/LCPA+) or no added PA groups (LFPA–

format between the two dietary groups.

limit their consumption of additional fats, sweets, and high-fat snacks.

Starting after the ffirst

pull-down, lower back extension and bent leg sit-ups.

Magnetic Resonance Imaging

randomly selected participants, we performed MRI measurement after 6 months of intervention.

TE1,1.19ms; TE2,2.3ms; FOV 520×440×80mm; 2×1.4×1mm voxel size). Four images

analysis range of 8 to 13 centimeters in a series of 16-26 slices on average, of 5mm thickness

pericardial fat was carefully excluded from analyses.27

Immulite automated analyzer, Diagnostic Products, coefficient of variation (CV)=2.5%]. Serum

University of Leipzig, Germany.

Monitoring and Motivating

quantified via a self-administered validated electronic 127 item food-frequency questionnaires

using an electronic self-reported validated PA questionnaires at baseline and after 6 and 18

months.44 To motivate compliance, participants were given a detailed individual report

after 6 and 18 month.33

assumption of a mean detectable pericardial-volume difference of 10cm3 between the time

nutrient changes within group. We used multivariate two-way

between genders were assessed by ANCOVA. Homeostasis-model-assessment-of insulin-

resistance (HOMA-IR) was calculated according to the following equation: insulin

medication use were negligible during th

decreased more than that of the LF diet group [mean-of-difference=-18.2% (95%CI=-25.2 to -

decreased more than in the MED/LC group [mean-of-difference=-10.1% (95%CI=-19.0 to -1.3)]

PA– groups (19.0MET/week vs 2.1MET/week; 95%CI=4.36-29.5

maintained similar adherence to their respective assigned diets (not shown).

moderate weight loss at 18 months, MED/LCPA+ decreased WC twice as much as LFPA–

(Supplemental figure 1).

Diverse Response of Adipose Tissues and Deposits to Different Lifestyle Interventions

estimate that an increase of one MET/week

hepatic fat [mean-of-difference=-1.56% absolute units; 95%CI:(-2.89 to -0.25)], on intra-

pericardial fat [mean-of-difference=-17.7mL;95%CI:(-31.2 to -4.39)] and on pancreatic fat

[mean-of-difference=-0.59% absolute units; 95%CI: (-1.10 to -0.08)] (Table 3), independent of

the dyslipidemia group (n=72).

Representative images (Figure 3) of changes in human fat depots/deposits in response to

(Supplemental table 4). MED/LC diet exhibited greater reductions in triglycerides (-

10.8mg/dl±28.0 vs -3.4mg/dl±43.8; P=0.040), TG/HDL ratio (-0.22±0.5 vs -0.15±0.47; p=0.023)

and an increase in HDL-c (+5.7mg/dl±7.1 vs +3.4mg/dl±7.5; P=0.009). No significant changes

results similar to the intention to treat analyses we have presented.

loss remained neutral expect of association with decreased leptin.

populations. However, we believe that similar strategies to maintain adherence cou

by restricting dietary fat intake had no such effect.50

University Medical Center, Beer-Sheva, Israel; 3Cardiac Imaging Unit, Department

Dimona, Israel; 5Department of Medicine, University of Leipzig, Germany; 6Channing Division

5. Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, Larsson A, Johansson L,