Age-Related Different Relationships between Ectopic Adipose Tissues and Measures of Central Obesity in Sedentary Subjects
et al. (2014) Age-Related Different Relationships between Ectopic Adipose Tissues and
Measures of Central Obesity in Sedentary Subjects. PLoS ONE 9(7): e103381. doi:10.1371/journal.pone.0103381
Age-Related Different Relationships between Ectopic Adipose Tissues and Measures of Central Obesity in Sedentary Subjects
Valeria Guglielmi 0
Luciano Maresca 0
Monica D'Adamo 0
Mauro Di Roma 0
Chiara Lanzillo 0
Massimo Federici 0
Davide Lauro 0
Paolo Preziosi 0
Alfonso Bellia 0
Paolo Sbraccia 0
Cordula M. Stover, University of Leicester, United Kingdom
0 1 Department of Systems Medicine, University of Rome ''Tor Vergata'' , Rome , Italy , 2 Diagnostic Imaging Department, Policlinico Casilino , Rome , Italy , 3 Cardiology Department, Policlinico Casilino , Rome , Italy
Accumulation of fat at ectopic sites has been gaining attention as pivotal contributor of insulin resistance, metabolic syndrome and related cardiovascular complications. Intermuscular adipose tissue (IMAT), located between skeletal muscle bundles and beneath muscle fascia, has been linked to physical inactivity, ageing and body mass index, but little is known about its relationship with the other AT compartments, in particular with increasing age. To address this issue, erector spinae IMAT, epicardial (EAT), intraabdominal (IAAT) and abdominal subcutaneous adipose tissue (SAT) were simultaneously measured by Magnetic Resonance Imaging (MRI) and related to waist circumference measurements and age in 32 sedentary subjects without cardiovascular disease (18 men; 14 women; mean age 48.5614 years). Fasting glucose, triglycerides and HDL-cholesterol were also assessed. We observed that, after dividing individuals according to age (# or .50 years), IMAT and EAT depots were significantly more expanded in older subjects (63.268.3 years) than in the younger ones (38.465.2 years) (p,0.001). Overall, both IMAT and EAT showed stronger positive associations with increasing age (b = 0.63 and 0.67, respectively, p,0.001 for both) than with waist circumference (b = 0.55 and 0.49, respectively, p,0.01 for both) after adjusting for gender. In addition, the gender-adjusted associations of IMAT and EAT with waist circumference and IAAT were significant in individuals #50 years only (p,0.05 for all) and not in the older ones. In contrast, no age-related differences were seen in the relationships of IAAT and SAT with waist circumference. Finally, serum triglycerides levels turned out not to be independently related with ectopic IMAT and EAT. In conclusion, the expansion of IMAT and EAT in sedentary subjects is more strongly related to age than waist circumference, and a positive association of these ectopic depots with waist circumference and IAAT amount can be postulated in younger individuals only.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its
Supporting Information files.
Funding: This work was supported by a grant from the Ministero dellUniversita` e della Ricerca(prot. 2010329EKE_003). The funder had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors confirm that the co-author Massimo Federici is a PLOS ONE Editorial Board member. The authors declare that this does not
alter adherence to PLOS ONE Editorial policies and criteria.
The regional distribution of adipose tissue (AT) plays an
important role in the development of metabolic and
cardiovascular diseases . Indeed, recent studies have suggested that the
location  and inherent properties [3,4] of excess AT, rather
than total body adiposity, influence the autocrine, paracrine and
endocrine effects of AT.
Whereas AT stored in subcutaneous depots is able to buffer the
energy excess and to protect against the development of the
metabolic syndrome (MS), intraabdominal adipose tissue (IAAT) is
part of a more complex phenotype including a dysfunctional
subcutaneous adipose tissue (SAT) and triacylglycerol deposition
at ectopic, undesirable sites such as liver , heart and skeletal
muscle . Excess IAAT accumulation and AT stored in ectopic
locations are closely related to clustering cardiometabolic
risk factors like chronic inflammation, liver insulin resistance,
hypertriglyceridemia and increased free fatty acid availability,
presence of small, dense LDL particles, and reduced HDL
cholesterol levels [3,7].
Thus, ectopic adipose depots resulting from this defect in energy
partitioning, have been gaining attention as potential and
regional contributors to insulin resistance and obesity
At present, epicardial adipose tissue (EAT), namely the ectopic
fat located subepicardically around both ventricles and along the
coronary arteries, is reported to correlate with BMI, waist
circumference and IAAT [8,9], and to contribute independently
to the development of coronary artery disease .
So far, few studies have focused on intermuscular adipose tissue
(IMAT), which includes the visible storage of lipids in adipocytes
located between the muscle fibers (also termed intramuscular fat)
and between muscle bundles (literally intermuscular) [11,12,13].
IMAT is unambiguously linked with increase in body weight
, physical inactivity or muscle disuse , and ageing [14,16].
Although recent studies suggest that IMAT accumulation may be
primarily the result of inactivity or muscle impairments rather
than ageing per se [17,18], therefore reflecting the importance of
physical activity intervention even in the elderly, the potential
relationship between central adiposity and IMAT accumulation,
especially across different ages, is not fully understood.
Moreover, although IMAT accumulation has been shown to be
significantly associated with insulin resistance [19,20] and
increased risk of type 2 diabetes , it is still unclear whether
or not IMAT can play an intermediary role in developing insulin
resistance, beyond its mere significance as marker of metabolic
Comparative studies demonstrated that magnetic resonance
imaging (MRI), which is a well-established, validated method for
estimation of AT and identification of its compartments [22,23],
has a higher sensitivity for identifying IMAT than computed
tomography, because, not being density based, provides estimates
not influenced by low density intra-myocellular lipids-enriched
lean tissue .
According to this background, the primary aim of our study was
to investigate the age-related association of erector spinae IMAT
with adiposity measures and gender, in a sample of sedentary
subjects. We additionally analyzed the relationships of
MRIassessed IMAT with EAT, IAAT, abdominal SAT and with
several common cardiometabolic risk parameters.
Materials and Methods
We enrolled 32 patients (18 men; 14 women) undergoing
cardiovascular MRI for arrhythmias (frequent ectopic ventricular
and sopraventricular beats) in order to exclude genetic
cardiomyopathy (hypertrophic cardiomyopathy, arrhythmogenic
cardiomyopathy and dilated cardiomyopathy) or acquired cardiac disease
(myocarditis, ischemic cardiac disease or inflammatory and
autoimmune diseases). All subjects, before undergoing MRI, had
been preliminarly evaluated by 12 leads electrocardiogram (EKG),
2D echocardiography, Holter EKG and stress test. Coronary
artery disease was excluded by maximal negative stress test, or
whenever indicated by coronary computed tomography
angiography or coronary angiography. Inclusion criteria were: no
pathological findings at the preliminary cardiologic evaluation
and no pathological evidence revealed by cardiac MRI assessment;
clinical history of normal fasting glucose; being non-smokers;
having stable weight and dietary habits for $6 months prior to the
study; having sedentary habits (based on self-report of no
participation in vigorous routine or structured exercise). We
excluded subjects affected by neoplasms, liver disease, renal
insufficiency or any other severe systemic disease.
Waist circumference was recorded as the average of two
measurements while the patients were standing, at midpoint
between the lowest rib and the iliac crest. Body mass index (BMI)
was calculated by dividing the weight (in Kg) by the square of
height (in meter). Blood pressure (BP) was measured in the sitting
position, with a standard, appropriately sized sphygmomanometer
cuff. Three measurements were averaged to calculate systolic and
Blood samples were obtained after overnight fast and glucose,
HDL-cholesterol, triglycerides were assessed by routine laboratory
techniques. MS was diagnosed according to IDF criteria .
Written informed consent was obtained from each patient
included in the study. The study was approved by the Ethical
Committee of the Fondazione Policlinico Tor Vergata (Rome),
and it conforms to the principles of the Declaration of Helsinki.
Magnetic Resonance Imaging
All patients underwent a standardized protocol including
quantification of EAT volume during cardiac MRI and
measurements of IMAT of rectus spinae, IAAT and SAT areas by two
single slice detections at L3L4 and L4L5 level. MRI data were
obtained with a Philips Intera 1.5 Tesla Achieva (Eindhoven, The
Netherlands) scanner. Image analysis of EAT, IAAT and SAT was
performed off-line using a stand-alone work station (Extended MR
WorkSpace 220.127.116.11, 2012 Philips Medical System). SliceOmatic
software (version 4.2; TomoVision, Montreal, Quebec, Canada)
was used to analyze images of IMAT. To assess inter-observer
reproducibility, a second independent observer repeated
measurements in each dataset using the same conventions.
EAT volume. For the assessment of EAT, we used a black blood
prepared T2-weighted multislice to obtain a transversal 4-chamber
view and short-axis images. Images parameters were as follows: time
of repetition  = 1600 ms, time to echo (TE) = 70 ms, slice
thickness = 4 mm, interslice gap (GAP) = 2 mm and field of view
(FOV) = 450 mm. EAT only included fat between the myocardial
border and the internal visceral layer of the pericardium. Areas of
EAT were traced manually on consecutive end-systolic short-axis
images beginning at the mitral valve and ending at the last slice
containing cardiac tissue. The areas obtained for each slice were
added together and multiplied by slice thickness to yield EAT volume
(Fig. 1 AC) .
IMAT area. A transverse section was obtained at L3L4 disk
level to measure IMAT of the erector spinae muscles (including
the multifidus, longissimus, and iliocostalis). The erector spinae
musculature was chosen for IMAT imaging analysis as unique
skeletal muscle site for which the accuracy of MRI measurements
of muscle tissue composition with corresponding histology in vivo
was assessed . The L3L4 level was selected for the analysis
because the muscle cross-sectional area has previously described as
the largest overall at this level . IMAT was defined as AT area
visible between muscle groups and beneath the muscle fascia (Fig. 1
A high-resolution T1-weighted TSE sequence was obtained and
the scanning parameters were TR = 100 ms, TE = 8 ms, slice
thickness = 3 mm, FOV = 256 mm. The gray-level intensity
(threshold value) of the AT in the SAT region was determined
and used as a reference . This threshold value was reduced by
20% to identify the IMAT threshold (SliceOmatic software).
IAAT and SAT areas. IAAT is defined as intraabdominal fat
bound by parietal peritoneum or transversalis fascia, excluding the
vertebral column and the paraspinal muscles; SAT is fat superficial
to the abdominal and back muscles. A breath-hold sequence was
used to minimize the effects of respiratory motion on the images. A
single image, located at L3L4 level, obtained using a
T1weighted FFE pulse sequence (TR = 97 ms, TE = 4.6 ms, slice
thickness = 5 mm, FOV = 445 mm), was chosen to assess IAAT
area, previously validated as good predictor of total IAAT volume
 (Fig. 1 E). The same sequence parameters except for
FOV = 256 mm were used to measure SAT area at L4L5 level
 (Fig. 1 F).
Statistical analysis was performed with the SPSS 19.0 software
(SPSS, Chicago). Descriptive statistics were given by means 6 SD.
The Kolmogorov-Smirnov test was used to verify quantitative
variables for normality distribution and non-normal distributed
parameters were logarithmically transformed before being used in
the subsequent parametric procedures. Comparisons between
groups were made using Students unpaired t-test. Relationships
between continuous variables were evaluated using Pearson partial
correlations including gender, waist circumference and IAAT as
potential confounders and resulting b coefficients were provided to
evaluate the strengths of the associations. For all these analysis a
pvalue ,0.05 based on two-sided test was considered statistically
The study population was constituted by 18 men and 14
women, aged 48.5614 years, with mean BMI of 25.663.9 Kg/m2
and waist circumference of 103.5614.8 cm. Whereas no
genderrelated differences were seen in EAT and IAAT depots, IMAT
was significantly more represented in women than in men (W:
925.46491.3 mm2; M: 501.16337 mm2; p,0.05).
All fat depots were positively correlated with both age and waist
circumference (Table 1), but the correlations coefficients revealed
distinct patterns. Indeed, IMAT and EAT were more strongly
associated with age than waist circumference, whereas SAT
followed an opposite trend, and IAAT resulted similarly associated
with both. The same distinct patterns were observed when looking
at the correlations of fat depots with BMI (IMAT: b = 0.47, p,
0.01; EAT: b = 0.46, p,0.01; IAAT: b = 0.63, p,0.0001; SAT:
b = 0.77, p,0.0001) instead of waist circumference.
We therefore divided our sample according to age (#50 and .
50 years), resulting in two subgroups significantly different for age
(p,0.001) and anthropometric measures, so that the older ones
had concomitantly higher waist circumference (p,0.01) and BMI
(p,0.001) than the youngers (Table 2). Similarly, IMAT, EAT,
IAAT and SAT amounts were significantly more represented in
older subjects compared to the younger ones (Fig. 2 AD).
Even though the older subjects enrolled in our sample study
were characterized by an overall greater amount of fat mass
compared to the younger ones, as reflected by differences in MRI
assessments and anthropometric parameters, the subsequent
regression analysis showed that IMAT and EAT quantitative
amounts were positively gender-adjusted associated with waist
circumference, but in younger subjects only (p,0.05 for both)
(Fig. 3 A,B). On the other hand, SAT and IAAT quantitative
depots showed great linear relationship with waist circumference
in both younger and older subjects (Fig. 3 C,D), even though the
strength of these associations was unexpectedly non significant for
IAAT in the older ones (p = 0.09).
In accordance to what observed with waist circumference
measures, both IMAT and EAT depots turned out to be
genderadjusted associated with IAAT in youngers (IMAT: b = 0.57, p,
0.05; EAT: b = 0.6, p,0.01), but not in subjects .50 years.
Interestingly, IMAT and EAT were not associated with SAT.
Of interest, the quantitative amounts of IMAT and EAT were
significantly correlated with each other, but once again in younger
subjects only (b = 0.6, p,0.01) (Fig. 4), whereas the same pattern
of relationship was not observed in the olders.
Finally, we observed that IMAT (b = 0.46, p,0.01) and IAAT
(b = 0.56, p,0.001), but not EAT and SAT, were positively
correlated with serum triglycerides, after adjusting for
hypolipidemic therapies. However, after adjusting for either waist
circumference or IAAT, the correlation between IMAT and triglycerides
EAT epicardial adipose tissue, IMAT intermuscular adipose tissue, IAAT intraabdominal adipose tissue, SAT subcutaneous adipose tissue.
BMI body mass index, BP blood pressure, EAT epicardial adipose tissue, IFG impaired fasting glucose, IMAT intermuscular adipose tissue, IAAT intraabdominal adipose
tissue, MS metabolic syndrome, SAT subcutaneous adipose tissue, T2D type 2 diabetes, TH therapies.
*significantly different (p,0.05). Data are expressed as mean 6 SD.
was no more significant (waist; b = 0.23, p = 0.2; IAAT: b = 0.19,
p = 0.3). Accordingly, patients with MS, who had greater IAAT
(MS: 101.3617.5 cm2; no-MS: 5769.2 cm2; p,0.05), SAT (MS:
290.4631.3 mg/dl; no-MS: 199.1624.3 mg/dl; p,0.05), fasting
glucose (MS: 110.269.6 mg/dl; no-MS: 9262.2 mg/dl; p,0.05)
and triglycerides levels (MS: 141.4612.2 mg/dl; no-MS
88.6610.2 mg/dl; p,0.01), showed a similar, but not significant,
trend for IMAT (MS: 848.36128 mm2; no-MS: 609.86100 mm2;
p = ns) and no difference in EAT (MS: 47.165.7 ml; no-MS:
In the present study we observed that IMAT, as well as EAT,
quantitative amounts are more strongly related with age than waist
circumference in sedentary individuals, and that in younger
subjects only (#50 yrs in our study population) a positive
association of IMAT depots with waist circumference measures
and IAAT amount can be postulated. In addition, no significant
and independent relationships were observed between ectopic
quantitative depots (IMAT and EAT) and circulating triglycerides
levels. Even though in our study population IMAT depots were
shown to be more represented in women than in men (p,0.05),
the associations reported above turned out to be not influenced by
gender. We hypothesize that such a gender-difference in IMAT
amount could have been driven by chance, since mid-calf and
total body IMAT have been previously reported to be equally
distributed among genders [20,30] and, in addition, no significant
gender-related differences in EAT, IAAT and SAT amounts were
detected in our sample study.
Even though IMAT could be conceivably more expanded with
increasing age, some previous studies have reported conflicting
results for this association . Plausible explanations for such a
discrepancy might rely on the fact that most studies in the field
have failed to account for activity levels and disease conditions or,
alternatively, have investigated on subjects in an extremely narrow
range of age. Consequently, as ectopic AT depots are known to be
strongly influenced by exercise, so that high physical activity is
proven to reduce IMAT amount both in younger and older master
athletes , we decided to apply no age restriction among
enrollment criteria of our study population, as well as to focus on
well established sedentary subjects in order to avoid this above
reported potential confounder on our analysis.
Interestingly, IMAT and EAT depots appeared to be more
strongly associated with age than waist circumference or BMI,
whereas similar trends were not reported for either IAAT or SAT
The reasons for these findings are not completely understood,
but it can be postulated that the distinct origin of ectopic fat, which
consists in the dysdifferentiation of muscle mesenchymal
progenitors, or the close anatomic contact of AT with muscular fibers,
which favors paracrine effects of myokines (IL-6, myostatin,
follistatin) and metabolites on the biology of the surrounding AT,
could account for distinct behaviors of intermuscular and
epicardial adipocytes comparing with those constituting IAAT
and SAT .
Our observations are in line with the notion that, with
increasing age, body fat becomes centralized and is redistributed
from subcutaneous to visceral compartments, even in healthy
people [31,32], suggesting that this redistribution could
additionally involve ectopic sites such as IMAT and EAT depots and
therefore lead to their greater expansion. Accordingly,
ageingassociated changes in AT distribution are a well-established
phenomenon irrespective of gender or race, accompanied by an
increased risk of MS, AT chronic inflammation and decreased
proliferation and differentiation of preadipocytes . In addition,
as older adults are often weaker than predicted by sarcopenia
alone  and high levels of leg IMAT are associated with
decreased muscle strength as well as muscle quality , the
increase of fat within skeletal muscle is likely to contribute further
to physical impairment and disability in the elderly. Similarly to
EAT, where the lack of interposed fascia allows pro-inflammatory
, cardiodepressant  and pro-fibrotic  factors to affect
myocardial structure and function, IMAT may promote
myosteatosis, myofibrosis  and functional impairment, by secreting
paracrine mediators and enhancing lipolysis rates within skeletal
muscle. Accordingly, both IMAT and Tumor Necrosis Factor-a
mRNA levels are increased in paretic limbs of stroke survivors
Noteworthy, we also observed that IMAT and EAT amounts
positively correlated with waist circumference and reciprocally
irrespective of gender, but in younger individuals (#50 yrs) only,
in contrast with what noted for SAT and IAAT which tended to
correlate similarly with waist circumference in both age groups (#
50 yrs and .50 yrs).
Even though all recruited subjects did not practice structured or
routine exercise, some evidence suggests that even changing the
way a muscle is used may play an important role in the level of
fatty infiltration seen with ageing: for instance, brisk walking,
which is less likely to be practiced by the olders, can decrease
IMAT amount . Besides, the higher loss percentage of IAAT
compared to IMAT and EAT after exercise-induced weight loss
may reflect distinct lipolytic properties [40,41], and allows to
speculate that ectopic compartments also respond differently to
We could additionally postulate that these age-related different
patterns could be consequent to modifications in sex hormones
levels, chronic stress-induced mild hypercortisolemia and
prolonged sympathetic nervous system activation, or even to
nutritional factors, across the ages . With regard to the latter,
fructose-sweetened beverages consumption may have a potential
effect on body fat distribution independent of its impact on overall
AT accretion, namely stimulating deposition of triglycerides in
ectopic sites by depot-specific modulation of lipogenic enzymes
Due to its association with age , physical inactivity ,
adiposity , muscle function impairment  and type 2
diabetes, IMAT has been suggested to be a risk factor for
obesityrelated diseases along with IAAT. The association with insulin
resistance and glucose metabolism has been previously reported
for erector spinae, thigh and total body IMAT [20,38,40,44,45]
irrespective of race, weight, height, and total skeletal muscle
volume . Furthermore, thigh IMAT was significantly
associated with increased systemic levels of inflammatory cytokines and
C-Reactive Protein, which have been linked to insulin resistance,
type 2 diabetes and age-related sarcopenia [46,47].
Nevertheless, it is currently unknown whether IMAT can play a
modifying role in the pathogenesis of insulin resistance or it is to be
alternatively considered a marker of metabolic dysfunction only.
The finding that IMAT amounts were positively correlated with
serum triglycerides, even though no causal relationship can be
affirmed, could suggest a contribution of IMAT in determining
obesity- and age-related metabolic diseases.
In accordance, IMAT is assumed to modulate blood flow to the
muscle, impair insulin diffusion capacity [20,48], and increase
local inflammation and lipolysis rates within the muscle. However,
after controlling for waist circumference or IAAT, the correlation
between IMAT and triglycerides was no more significant,
highlighting the greater relevance of IAAT in directly influencing
the metabolism, putatively through its greater extent and unique
anatomic location, which allow the release of free fatty acids into
the portal system to the liver and pancreas.
Finally, we acknowledge some study limitations, mainly related
to the cross-sectional design which does not allow to assess
causeeffect relationships, and to the small sample size which precludes
to address other potential confounders using covariate analysis,
e.g. the interaction between age and waist circumference in their
relationships with IMAT or EAT. The study is also adversely
affected by the lack of any direct measure of insulin resistance,
which would have been useful to better characterize our study
population from a metabolic perspective, although the presence of
MS diagnosed according to IDF criteria can provide indirect
information about insulin resistance status . On the other
hand, we believe that major strengths of our study derive from the
use of MRI, namely the gold standard technique to assess AT
quantitative distribution and from the opportunity to include
individuals with known sedentary habits and in a wide distribution
In summary, herein we report that in sedentary subjects without
cardiovascular disease IMAT as well as EAT depots are related
with increasing age to a greater extent than observed with waist
circumference, and that the positive association of IMAT amount
with waist circumference and IAAT is likely to be significant for
younger individuals only. Further research is needed to better
clarify these issues and, more generally, to better characterize the
role of ectopic AT depots in the pathophysiology of
We are grateful to Prof. Alessandra Nardi for statistical advice. We also
thank Amleto Alberico, Stefano Bonetti, Gianluca Campo, Domenico De
Rosa e Giorgio Sebastiano for technical assistance in MRI scan execution.
Conceived and designed the experiments: VG. Performed the experiments:
VG LM. Analyzed the data: VG LM M. Di Roma AB. Contributed
reagents/materials/analysis tools: CL PP. Contributed to the writing of the
manuscript: VG LM M. DAdmao MF DL AB PS.
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