REVIEW
The genetics of fat distribution
Dorit Schleinitz & Yvonne Böttcher & Matthias Blüher &
Peter Kovacs
Received: 1 November 2013 /Accepted: 18 February 2014 /Published online: 16 March 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract Fat stored in visceral depots makes obese individuals
more prone to complications than subcutaneous fat. There
is good evidence that body fat distribution (FD) is controlled
by genetic factors. WHR, a surrogate measure of FD, shows
significant heritability of up to ∼60%, even after adjusting for
BMI. Genetic variants have been linked to various forms of
altered FD such as lipodystrophies; however, the polygenic
background of visceral obesity has only been sparsely investigated
in the past. Recent genome-wide association studies
(GWAS) for measures of FD revealed numerous loci
harbouring genes potentially regulating FD. In addition, genes
with fat depot-specific expression patterns (in particular subcutaneous
vs visceral adipose tissue) provide plausible candidate
genes involved in the regulation of FD. Many of these
genes are differentially expressed in various fat compartments
and correlate with obesity-related traits, thus further
supporting their role as potential mediators of metabolic alterations
associated with a distinct FD. Finally, developmental
genes may at a very early stage determine specific FD in later
life. Indeed, genes such as TBX15 not only manifest differential
expression in various fat depots, but also correlate with
obesity and related traits. Moreover, recent GWAS identified
several polymorphisms in developmental genes (including
TBX15, HOXC13, RSPO3 and CPEB4) strongly associated
with FD. More accurate methods, including cardiometabolic
imaging, for assessment of FD are needed to promote our
understanding in this field, where the main focus is now to
unravel the yet unknown biological function of these novel
‘fat distribution genes’.
Keywords Adipose tissue . Fat distribution . Genetics .
GWAS
Abbreviations
CT Computerised tomography
eQTL Expression quantitative trait locus
FD Fat distribution
GWAS Genome-wide association studies
SNP Single nucleotide polymorphism
WC Waist circumference
Introduction
Obesity increases the individual risk for type 2 diabetes,
dyslipidaemia, fatty liver disease, hypertension and cardiovascular
disease [1]. However, obesity itself does not necessarily
lead to these comorbidities [2–4]. Adipose tissue as a highly
active endocrine organ is distributed at several body sites. As
shown in early work by Kissebah [5] and Björntorp [6] on
anthropometric correlates of fat distribution (FD) and clinical
outcomes such as metabolic and cardiovascular diseases, fat
stored in visceral adipose depots makes obese individuals
more prone to these complications than fat distributed subcutaneously.
The importance of visceral adipose tissue in the
pathophysiology of insulin resistance, dyslipidaemia and cardiovascular
disease was further supported by Matsuzawa et al
[7] and Despres et al [8] in their pioneering work using
imaging measurements of body FD. In this context, reduction
in subcutaneous fat mass by liposuction does not ameliorate
Dorit Schleinitz and Yvonne Böttcher contributed equally to this study.
Electronic supplementary material The online version of this article
(doi:10.1007/s00125-014-3214-z) contains peer-reviewed but unedited
supplementary material, which is available to authorised users.
D. Schleinitz :Y. Böttcher :M. Blüher :P. Kovacs (*)
Integrated Research and Treatment Center (IFB) AdiposityDiseases,
University of Leipzig, Liebigstr. 21, 04103 Leipzig, Germany
e-mail: peter.kovacs@medizin.uni-leipzig.de
M. Blüher
Department of Medicine, University of Leipzig, Leipzig, Germany
Diabetologia (2014) 57:1276–1286
DOI 10.1007/s00125-014-3214-z
circulating metabolic and inflammatory variables [9]. On the
other hand, visceral fat mass reduction by omentectomy combined
with gastric banding results in long-term beneficial
effects on glucose metabolism and insulin sensitivity [10].
The relationship of ectopic visceral fat deposition with metabolic
and cardiovascular diseases may be at least partially
explained by intrinsic properties of visceral as opposed to
subcutaneous adipose tissue with regard to decreased insulin
sensitivity, lower angiogenic potential, increased lipolytic activity,
different cellular composition and the expression of
genes regulating adipocyte function [11]. In addition, the
visceral fat depot drains into the portal vein, thus exposing
the liver to undiluted metabolites, cytokines and adipokines
released from visceral fat, which could further contribute to an
increased cardiometabolic risk [12]. Taken together, dysfunction
of adipose tissue and ectopic fat seems to play an important
role in the individual risk of developing obesityassociated
metabolic and cardiovascular complications. However,
it is noteworthy that recent imaging studies, including
the Framingham Heart Study, have highlighted not only the
importance of visceral adipose tissue, but also other ectopic fat
depots such as liver or renal fat [13, 14].
Measurement of fat distribution
In clinical practice, waist circumference (WC) and WHR are
widely used variables used to determine regional FD. Imaging
techniques such as computerised tomography (CT) or whole
body MRI scan are considered the gold standard for evaluating
adipose tissue [7, 8]. To measure the visceral and subcutaneous
abdominal areas, a CTor MRI scan is usually taken at
the level of L4–L5 or the umbilicus, using an attenuation
range between −30 and −190 Hounsfield units [11]. The ratio
of visceral to subcutaneous adipose tissue has been shown to
be strongly correlated with impaired glucose and lipid metabolism
in obese individuals [15]. This ratio, with a cut-off at
0.4, allows stratification of obese individuals into visceral
(>0.4) and subcutaneous (<0.4) groups [15]. Abdominal sagittal
diameter derived from CT or MRI images has also been
used to determine abdominal FD [11]. Applying CT scans in
403 volunteers, Lemieux et al proposed cut-off values corresponding
to an accumulation of visceral adipose tissue of
130 cm2
, which is strongly related to metabolic disorders:
WHR of 0.94 in men and 0.88 in women, a waist girth of
∼95 cm and sagittal diameters of 22.8 cm in men and 25.2 cm
in women [16]. It is noteworthy that, despite continuous
technological advances in the measurement of FD, Lemieux
et al have suggested the use of simultaneous measurement of
WC and fasting triacylglycerol (hypertriglyceridaemic waist)
as a simple screening tool to identify men characterised by the
atherogenic metabolic triad (hyperinsulinaemia, elevated
apolipoprotein B [ApoB], small, dense LDL particles) and at
high risk for coronary artery disease [17].
Which factors determine fat distribution?
Together with genetic factors, the main predictors of visceral
fat and FD are age, sex, total body fat content and energy
balance [11]. Visceral fat mass increases with age independently
of total body fat mass, but this is more pronounced in
men than in women [11]. Sex plays a specific role, and this has
also been reflected by differentiating obesity into android
(‘apple’) and gynoid (‘pear’) types [18]. In this context, it
has to be mentioned that sex hormones may modulate adipose
tissue accumulation in a depot-specific manner. For example,
declining oestrogen and/or excess androgens in postmenopausal
women may facilitate fat partitioning from the periphery
to the intra-abdominal cavity [19]. Alterations in endocrine
signalling may also contribute to changes in FD. For
instance, Cushing’s syndrome is characterised by redistribution
of fat from peripheral to central parts of the body [11].
Moreover, visceral fat mass in men is negatively associated
with testosterone and sex-hormone binding globulin (SHBG)
levels [20].
Despite facilitating the intra-abdominal accumulation of
fat, a positive energy balance does not appear to be a major
determinant of visceral fat mass. Energy intake/supply correlated
with subcutaneous fat in monozygotic twins under
hyper-energetic nutrition, yet the variation in visceral fat did
not exceed 10% [21]. In contrast, there is good evidence that
body weight loss results in an over-proportional reduction of
the visceral fat mass [22], which might, at least in part, be
explained by higher lipolytic capacity of visceral compared
with subcutaneous fat [11].
In addition, it is likely that environmental factors either
directly, or in genetically susceptible individuals, contribute to
individual differences in FD (Fig. 1). For example, data from
rodent studies suggest that food contaminants, particularly
those with endocrine signalling capacities, may also cause
ectopic fat accumulation in the liver and visceral fat depots
[23]. There is also good evidence in humans that sugarsweetened
beverages promote the accumulation of visceral
adiposity [24]. Moreover, as suggested by Björntorp, stress
mediated by psychosocial and socioeconomic handicaps, depressive
and anxiety traits, alcohol and smoking may lead to
neuroendocrine perturbations followed by abdominal obesity
with its associated comorbidities [25].
Genetic background of fat distribution
There is good evidence that not only obesity but also FD is
controlled by genetic factors, and that this is independent of
Diabetologia (2014) 57:1276–1286 1277
BMI and overall obesity [26, 27]. Studies estimating heritability
of WHR have provided eminent proof for a genetic
background to FD, showing that this trait is heritable with
estimates ranging from 22% to 61% even after accounting for
obesity [26–30]. In one of the pioneering works in this field,
Bouchard et al showed in identical twins that within-pair
similarity was particularly evident for changes in regional
FD and amount of abdominal visceral fat, with significantly
greater variance among pairs than within pairs, thus strongly
suggesting the involvement of genetic factors [21]. In the
Quebec Family Study, heritability estimates reached 56% for
abdominal visceral fat, while only 42% heritability was estimated
for subcutaneous fat [31]. These data suggested a
strong genetic influence on the familial aggregation in abdominal
fat, independent of total body fat mass, and clearly indicated
that genetic factors seem to have a greater effect on
abdominal visceral fat than on abdominal subcutaneous adipose
tissue. Supporting the earlier studies, heritability estimates
of between 83% and 86% for total fat, and between
71% and 85% for regional fat (trunk, lower body, trunk/lower
body) have been reported in young and elderly Danish twins
[32]. Considering that variation in FD during adolescence is
correlated with FD in adulthood, Peeters et al estimated the
relative contribution of genes and environment to the stability
of subcutaneous FD from early adolescence into young adulthood
in the Leuven Longitudinal Twin Study [33] and showed
that the distribution of trunk to extremity adipose tissue is
under strong genetic control (>75%) in boys and girls.
Since some individuals are genetically predisposed to store
abdominal fat in the visceral rather than in the subcutaneous
depot, the above-mentioned studies also implied that these
individuals are at higher genetic risk of manifest metabolic
complications associated with visceral obesity [31].
Conditions of altered fat distribution
Conditions such as steatopygia and lipodystrophies also support
the role of genetics in FD. There are obvious differences
in body FD as humans gain or lose weight. This is extremely
profound in certain ethnic groups such as the Khoikhoi (previously
known as Hottentots) in southern Africa, whose women
show excessive accumulation of fat in the buttocks [34].
Lipodystrophies with abnormal regional fat deposition provide
further convincing evidence for the role of genetics in FD
[35]. For instance, for congenital generalised lipodystrophy,
which is characterised by a partial or complete loss of any
adipose tissue, mutations in four genes, AGPAT2, BSCL2,
CAV1 and PTRF, leading to disturbances in either lipid storage
(AGPAT2) or lipid homoeostasis (CAV1, PTRF, BSCL2) have
been postulated to be causative [36–39]. One of the most
prominent genes causing familial partial lipodystrophy encodes
lamin A/C (LMNA) whose mutations result in familial
partial lipodystrophy of the Dunnigan type, which is
characterised by a loss of subcutaneous adipose tissue in the
extremities and trunk, without loss of visceral, neck, or facial
fat [40, 41]. Patients with Dunnigan-type familial partial
lipodystrophy suffer post puberty from regional and progressive
adipocyte degeneration, which is often accompanied by
profound insulin resistance and diabetes [42]. It has been
demonstrated in mice that, rather than involving a loss of fat,
the major mechanism contributing to the lack of fat
Fat distribution
Environment
(epigenetic modifications?)
Genes/genetic variants
GWAS Candidate genes
Genes from
monogenic forms
of altered FD
(LMNA?)
Developmental
genes
LYPLAL1, VEGFA,
NFE2L3, GRB14–
COBLL1, DNM3–
PIGC, ITPR2–SSPN,
LY86, ADAMTS9,
ZNRF3–KREMEN1,
NISCH–STAB1, MC4R,
NRXN3, TFAP2B,
MSRA
Fat depot-specific
expression
ADRB3, APOB, GR, LPL,
PAI1, RBP4, LEP, IL6,
AGT, PPARG, CB1R,
FASN, SIRT1
HOXC13,
TBX15,
RSPO3,
CPEB4
Age, sex,
endocrine signals
GLYP4,
HOXA5,
SHOX2, EN1,
HOXC8,
HOXC9
BMPR1A
BMPR2
Fig. 1 Genetics of FD: strategies
to identify genes involved in fat
distribution and potential
mechanisms contributing to
variability in FD. GWAS provide
a major tool for identification of
novel genes associated with FD
measures, such as WHR.
Candidate gene strategies rely on
the investigation of genes with fat
depot-specific mRNA expression.
In addition, genes known to be
involved in the pathophysiology
of other forms of altered fat
distribution, such as
lipodystrophies, are potential
candidates (e.g. LMNA).
Developmental genes represent a
unique group of genes that is not
only supported by their
physiological role but also by
GWAS. CB1R is also known as
CNR1
1278 Diabetologia (2014) 57:1276–1286
accumulation is likely to be an altered renewal capacity of the
adipose tissue, which could be attributed to the disturbed
differentiation of pre-adipocytes into functional adipocytes
[43]. Interestingly, common variants in LMNA have been
shown to contribute to the polygenic background of type 2
diabetes and obesity [44–46], making LMNA a plausible candidate
for involvement in the pathophysiology of visceral
obesity (Fig. 1).
Familial multiple lipomatosis is another condition of altered
FD that is characterised by the presence of multiple
lipomas on the body. Although an autosomal-dominant inheritance
has been proposed [47], information on the genetic
background of lipomatosis is sparse and research has so far
focused on HMGA2 and its fusion partners LPP and LHFP
[48–50]. Of note, transgenic mice expressing truncated
Hmga2 still retaining the three AT-hook domains are
characterised by a giant phenotype and hyperplasia of white
adipose tissue [51] whereas, on the other hand, HMGA2
knockout mice present a pygmy phenotype with hypoplasia
of white adipose tissue [52]. Likewise, a lack of HMGA2
impairs lineage commitment of stem cells toward preadipocytes,
further supporting the role of HMGA2 in adipogenesis
[53].
Candidate genes for regulating fat distribution
The classical approach to examining the heterogeneity of
adipose tissue is based on comparisons of protein and gene
function and expression between the visceral and subcutaneous
fat depots. Differential gene expression between visceral
and subcutaneous adipose tissue points to genetic heterogeneity
and, therefore, its investigation represents a promising path
to reveal candidate genes involved in the regulation of FD.
Indeed, there are numerous genes with differential expression
between visceral and subcutaneous adipose tissue, such as
ADRB3 [54], APOB [55], GR (also known as NR3C1) [56],
LPL [57], PAI1 [58], RBP4 [59], LEP [60], IL6 [61], AGT [60]
or PPARG [62] (Fig. 1). It has been postulated that genetic
variants in these genes may contribute to ectopic visceral
storage [63]. Moreover, many of these genes, notably ADRB3,
APOB, LPL, RBP4, LEP, IL6, APM1 and PPARG, are not only
differentially expressed in various fat depots, but are also
associated with traits related to obesity, such as insulin resistance
or adipokine levels. Even though it is unclear whether
differential expression is a cause or consequence of obesity
and/or FD pattern, it might be postulated that changes in gene
expression or function caused by genetic variants may link
metabolic alterations to obesity. Consistent with this hypothesis,
it was demonstrated that polymorphisms in genes such as
FASN, BMPR1A, BMPR2 and RBP4 were associated not only
with WHR and BMI-related traits but also with their transcript
levels, indicating that the single nucleotide polymorphisms’
(SNPs’) effects are mediated through regulation of gene expression
[64–67]. These findings clearly indicate potential
functionality of the identified polymorphisms in the regulation
of FD. It has to be acknowledged, however, that in general,
early candidate gene studies were mostly underpowered and
the genotype–phenotype associations would not have withstood
the currently accepted genome-wide statistical significance
levels. Nevertheless, they undoubtedly deserve attention
as they may still represent very promising targets contributing
to a better understanding of the complex aetiology of
obesity-related complications, and might even pave the way
for novel treatment strategies in metabolic disorders.
For example, given its biological role in metabolism,
PPARG (the gene encoding peroxisome proliferatoractivated
receptor γ) is one of the most prominent candidates
for involvement in modulating FD. Treatment of type 2 diabetes
with thiazolidinediones, which activate PPARG selectively,
increases fat partitioning to the subcutaneous adipose
depot [68] and may also reduce visceral fat volume [69].
Therefore, it may not be surprising that the genetic variant
predicting a Pro115Gln change in PPARG has also been
investigated intensively in relation to FD and was not only
found in extremely obese subjects but also shown to promote
adipocyte differentiation [70]. In contrast, the Pro12Ala variant
in PPARG is associated with lower BMI, better insulin
sensitivity and reduced risk of type 2 diabetes [63]. Although a
significant PPARG gene–sex interaction was observed in the
modulation of BMI, fat mass and blood pressure for
Pro12Ala, it was also associated with WC independently of
BMI and sex [71]. Consistently, the polymorphism was associated
with WHR and visceral and subcutaneous fat mass in
Korean women, although the data suggested that the gene has
a larger impact on subcutaneous than visceral adipose tissue
[72].
As sirtuin 1 (SIRT1) is an important regulator of energy
metabolism through its impact on glucose and lipid metabolism,
genetic studies have been performed to test the effects of
genetic variation in SIRT1 on adiposity. A Belgian case–
control association study involving 1,068 obese patients and
313 lean controls suggested that genetic variants of SIRT1
increase the risk for obesity, and that the SIRT1 genotype
correlates with visceral obesity variables (WC, WHR and
visceral and total abdominal fat) in obese men [73].
Genome-wide association studies
By using the latest advances in high-throughput technologies
as well as statistical approaches for well-powered genomewide
association studies (GWAS), numerous novel and, from
a biological point of view, unexpected genes/loci have been
identified over the last couple of years. One of the earliest
studies revealed an association between rs12970134 and WC
Diabetologia (2014) 57:1276–1286 1279
in individuals of Indian-Asian or European ancestry [74]. The
SNPs have been mapped near MC4R, which is known to be
predominantly involved in monogenic obesity [74]. Since
then, MC4R has remained one of the major WC-associated
loci, conferring a relatively large effect size of 0.88 cm per risk
allele [74]. In addition, a few other loci related to WC, including
the neurexin 3 gene (NRXN3), have been discovered [75].
Since the effect of the associated variant was markedly attenuated
when adjusting for BMI, it is likely that NRXN3 is
involved in regulating overall obesity rather than WC [75],
which is in line with previous studies showing NRXN3, to be
related to obesity and BMI [76].
The first meta-analysis of GWAS relating to WC and WHR
was conducted by Lindgren et al and suggested a role for
genetic factors in the regulation of both WC and WHR [77].
Genetic variants within TFAP2B and near MSRAwere strongly
associated with visceral fat accumulation (WC). Furthermore,
the authors identified variants ∼250 kb downstream of
LYPLAL1 with strong sex-specific variability, as associations
with WHR were restricted to women only. In line with the
Lindgren meta-analysis, a recent study conducted with 32
GWAS for WHR adjusted for BMI (up to 77,167 participants),
and following up 16 loci in an additional 29 studies (up to
113,636 participants), uncovered 13 loci associated with
WHR (RSPO3, VEGFA, TBX15–WARS2, NFE2L3, GRB14–
COBLL1, DNM3–PIGC, ITPR2–SSPN, LY86, HOXC13,
ADAMTS9, ZNRF3–KREMEN1, NISCH–STAB1, CPEB4)
and confirmed the known association signal at LYPLAL1, with
effect sizes reaching 0.059 per risk allele in women (Fig. 2;
electronic supplementary material [ESM] Table 1) [30, 77]. A
recent GWAS including up to 263,407 individuals of European
ancestry replicated associations with WHR for RSPO3,
LY86, LYPLAL1 and COBLL1 [78]. Altogether, the GWAS
findings indicate a strong genetic background for WHR regulation,
independently of overall obesity.
In addition to GWAS for WHR, several studies used more
precise measures of FD, such as visceral and subcutaneous fat
area measured by CT [79, 80]. These GWAS revealed additional
variants implying the value of more accurate measurements in
unravelling novel polymorphisms contributing to the genetic
control of FD. In particular, Fox et al provided strong evidence
for an association of a novel locus with visceral adipose tissue
near THNSL2 in women [80]. Moreover, using the ratio of
visceral to subcutaneous adipose tissue, significant associations
were replicated for seven of the previously reported WHR loci
(after adjusting for BMI) [30, 80]. Given the known limitations
of WHR as a measure of FD, particularly based on the fact that,
for a given WHR value, there may be large variation in the level
of abdominal visceral adipose tissue, the data from Fox et al
clearly demonstrate the need for including more accurate phenotypes
of regional FD in future genetic analyses.
Although most of the previous GWAS were conducted in
cohorts of European ancestry, recent studies have replicated
the previously identified associations in various ethnic populations
[81, 82]. While confirming six of the 14 loci described
above for WHR (TBX15–WARS2, GRB14, ADAMTS9, LY86,
RSPO3, ITPR2–SSPN), two novel regions have been shown
to associate significantly with WC and WHR (LHX2 and
RREB1, respectively; both adjusted for BMI) in individuals
of African ancestry [81]. Furthermore, recent analyses of the
14 WHR loci confirmed the potential role in FD for LYPLAL1
and NISCH in a Japanese population [82].
It is of note that a recent GWAS identified a novel SNP near
TRIP2 associated with pericardial fat [83]. The variant
rs10198628 was exclusively associated with pericardial fat
in a multi-ethnic survey, without any further evidence of
association with visceral adipose tissue or BMI. The authors
provided further evidence for an expression quantitative trait
locus (eQTL) suggesting that the association of the lead
variant close to TRIP2 might be mediated by its altered gene
expression [83].
Sexual dimorphism in GWAS The fact that seven of the loci
identified by Heid et al (RSPO3, VEGFA, GRB14, LYPLAL1,
ITPR2–SSPN, ADAMTS9, HOXC13) (Fig. 2) exhibited significantly
stronger effects on WHR in women than in men
might explain why all the 14 loci explained 1.34% of the
variance in WHR in women but only 0.46% of the variance
in men [30]. The sexual dimorphism in FD gained further
support from a very recent large-scale study comprising
133,723 individuals in the initial meta-analysis of GWAS
and 137,052 individuals in subsequent replication stages
[84]. Specifically, significant sex-related differences were replicated
for four of the 14 previously reported WHR-associated
loci (adjusted for BMI) near GRB14–COBLL1, LYPLAL1–
SLC30A10, VEGFA and ADAMTS9 (Fig. 2) [30, 84]. Moreover,
three novel loci were identified for WC (near MAP3K1)
and WHR (adjusted for BMI) (near HSD17B4 and PPARG)
(Fig. 2), whereas no evidence for sex-specific differences was
found for other anthropometric measures. The observed sexual
dimorphism may not be surprising when considering that
sex differences manifest not only in WHR per se but also in
the extent of genetic effects influencing variation in body
composition. Although there is a shortage of studies systematically
investigating sex differences in the genetic architecture
of body composition, Zillikens et al showed that genetic
variance was significantly higher in women for waist, hip and
WHR in the Erasmus Ruphen Family study, thus suggesting
that genes account for more phenotypic variance of FD in
women than in men [85]. The above-mentioned GWAS
strengthen the conclusions of the Erasmus Ruphen Family
study and clearly imply the tremendous importance of sexspecific
analyses in studies aimed at pinpointing the genetic
architecture of complex traits such as FD. Nevertheless, it has
to be kept in mind that genetic determinants of body composition
may be modulated by sex-specific hormonal,
1280 Diabetologia (2014) 57:1276–1286
environmental and nutritional factors [85], which may at least
partially explain the observed sex-related differences in genetic
effects on FD.
Functional evidence for the role of genes identified by
GWAS In contrast to the variants related to obesity and BMI,
which are mostly expressed in the brain, the vast majority of
the WHR-related genes identified by GWAS are predominantly
expressed in peripheral tissues [76, 86, 87]. However, a
functional role could be assigned to only a handful of candidate
genes, predominantly involved in adipogenesis (TBX15),
early embryonic development (HOXC13), angiogenesis
(VEGFA, RSPO3 and STAB1), lipase activity (LYPLAL1) or
lipid biosynthesis (PIGC) (reviewed in [30]). With regard to
the potential function of the genes identified, and apart from
the sex-specific association signals, another important aspect
of the GWAS carried out by Heid et al was the identification of
eQTLs for six WHR-associated SNPs (rs984222 for TBX15
mRNA in omental adipose tissue; rs1055144 for AA553656
mRNA, rs10195252 for GRB14 mRNA and rs4823006 for
ZNRF3 mRNA in subcutaneous adipose tissue; rs1011731 for
PIGC mRNA in lymphocytes; rs6784615 for STAB1 mRNA
in blood) [30]. At these loci, the WHR-associated SNPs
explained the majority of the association between the most
significant eQTL and the gene transcript. Moreover, mRNA
of the five potential FD-related genes (RSPO3, TBX15,
ITPR2, WARS2 and STAB1) was differentially expressed between
gluteal and abdominal subcutaneous adipose tissue. In
follow-up studies, these data could be strengthened by demonstrating
fat depot-specific differences in mRNA expression
between subcutaneous and visceral adipose tissue for all six
genes mapped within the reported eQTLs [88]. Whereas only
PIGC, ZNFR3 and STAB1 mRNA expression in subcutaneous
adipose tissue correlated nominally with WHR, mRNA
expression of all six genes in at least one of the fat depots
correlated significantly with visceral and/or subcutaneous fat
area. Finally, the rs10195252 T-allele was nominally associated
with increased GRB14 subcutaneous mRNA expression,
suggesting that the association with WHR might be mediated
by the SNP effects on mRNA expression levels. GRB14
appears to be an appealing gene as it binds to the insulin
receptor and its expression is enhanced in patients with
type 2 diabetes. Moreover, Grb14-deficient mice (Grb14−/−
)
manifest enhanced insulin signalling in liver and skeletal
muscle, improved glucose homeostasis and increased body
weight, mainly due to increased lean mass, on a normal diet
[89, 90]. When put on a high-fat diet, the Grb14−/−
mice showed
an increase in fat mass, detected by dual-energy X-ray absorptiometry
(DEXA), which was not, however, accompanied by a
parallel increase in epididymal fat mass [91]. Consequently, as
postulated by Holt et al, it could either be the case that small
differences in numerous adipose depots may lead to a significant
overall difference in fat mass or, alternatively, that there may be
depot-specific differences in fat accumulation with no change
observed for the epididymal depot [91].
Developmental genes in the regulation of fat distribution
Fat depot-specific expression of developmental genes provides
further support for the strong genetic background of
FD [92]. It has been observed in both rodents and humans
that visceral adipose tissue is characterised by higher mRNA
levels of HoxA5, HoxA4, HoxC8, Gpc4 and Nr2f1, whereas
subcutaneous fat has higher levels of HoxA10, HoxC9, Twist1,
Tbx15, Shox2, En1 and Sfpr2. Even more importantly, such
variability in gene expression is also found in pre-adipocytes
Fig. 2 Sex-specific effect sizes of
WHR-associated loci: effect sizes
of all genome-wide significant
WHR loci meta-analysed by (1)
Heid et al [30] and by (2) Randall
et al [84]. The data are ordered by
effect sizes in women and
reported for the combined stages
of analyses. (3) Genome-wide
significance in women; (4)
genome-wide significance in
men; black bars, women; white
bars, men
Diabetologia (2014) 57:1276–1286 1281
derived from different fat depots in rodents and humans, and
appears to be intrinsic, since it persists during in vitro culture
and differentiation [92, 93]. This may suggest that different
mesodermal regions might give rise to precursors in different
adipose depots, and might so contribute to biological differences
between visceral and subcutaneous adipose tissue. In
support of this, Gesta et al have shown that mRNA expression
profiles of Tbx15, Gpc4 and HoxA5 not only differ between
various adipose depots but also strongly correlate with BMI,
WHR or visceral fat mass and subsequent metabolic alterations
in mice as well as humans, suggesting that genetic
differences in regulation of the development and differentiation
of adipocytes could at least partially explain the development
of visceral obesity [92, 94].
It is noteworthy, however, that depot-specific differences
have been observed even within subcutaneous adipose tissue,
as demonstrated recently by Karastergiou et al, who investigated
depot- and sex-dependent differences in gene expression
in human abdominal and gluteal subcutaneous adipose tissue
[95]. There was again strong evidence for differential regulation
of mRNA expression of homeobox genes in both sexes, implying
that developmentally programmed differences may contribute
to the distinct phenotypic characteristics of peripheral fat
[95]. Consistently, a unique expression pattern of developmental
genes has been previously described by Yamamoto et al
for Shox2, En1, Tbx15, Hoxa5, Hoxc8 and Hoxc9 in several
subcutaneous and intra-abdominal white and brown adipose
tissue depots in mice under obese and in fasting conditions
(Fig. 1) [96]. With regard to gene function, it has been shown
very recently that SHOX2, whose expression levels in human
subcutaneous adipose tissue positively correlate with visceral
obesity, regulates lipolysis via increasing ADRB3 expression,
thus suggesting its role in adipocyte biology [97].
Epigenetics and other aspects
It should be noted that, despite recent advances in the field of
high-throughput genetic analyses resulting in a number of
novel polymorphisms associated with WHR, these polymorphisms
can only explain a small proportion of phenotypic
variance and genetic heritability in FD [30]. Therefore, other
players such as non-coding RNA or DNA methylation need to
be acknowledged as possible regulators of FD (Fig. 1).
Epigenetic modifications, such as DNA or histone methylation,
modify long-term gene expression and seem to provide
plausible mechanisms for adapting the genome to environmental
circumstances. It has been shown that nutritional oscillations
in certain developmental periods of life may increase
susceptibility to overweight and related diseases. Perinatal
programming of the genome based on prenatal and neonatal
overfeeding contributes to obesity and diabetes in later life
[98]. It is also increasingly appreciated that there is an
association between maternal nutrition during pregnancy and
intrauterine development of fetal body composition and subsequently
FD later in life [99]. More importantly, body composition
and adverse FD may be modifiable via nutritional
intervention in the mother [99]. As mentioned above, the
strong adipose tissue-specific expression patterns of genes
playing a fundamental role in early development were strikingly
found to be preserved from one pre-adipocyte to the next
over several generations [93, 100], implying the existence of
yet unknown mechanisms maintaining the expression profiles
over time [101]. This is not only supported by demonstrating
that white and brown adipose tissue originate from independent
precursor cells [102] but also by showing distinct methylation
profiles for white and brown pre-adipocytes [103]. In a
genome-wide methylation analysis of eight different adipose
depots in three pig breeds living within comparable environments,
but displaying distinct fat levels, Li et al investigated
the systematic association between anatomical locationspecific
DNA methylation status of different adipose depots
and obesity-related phenotypes [104]. Using methylated DNA
immunoprecipitation sequencing, the authors showed that,
compared with subcutaneous adipose tissue, visceral and
intermuscular adipose tissue, which are the metabolic risk
factors of obesity, were primarily associated with impaired
inflammatory and immune responses. By presenting functionally
relevant methylation differences between different adipose
depots, the study supports the role of epigenetics in the
regulation of FD. Epigenetic studies on animal models are
now being complemented by human studies, which bring
further evidence for the potential role of epigenetics in the
pathophysiology of adverse FD. For instance, a recent study
by Huang et al described a positive correlation between
IGF2–H19 DNA methylation levels and ultrasound-derived
measures of subcutaneous fat thickness in young adults [105].
Furthermore, DNA methylation levels at the LEP promoter
were shown to be related to its tissue distribution [106]. As
mutations in LMNA represent a major determinant of monogenic
forms of altered FD, it is of interest that a recent study
proposed that lamin A/C–promoter interactions specify chromatin
state-dependent transcription outcomes [107]. Although
these studies clearly suggest the role of epigenetic modifications
in FD, the potential mechanistic chains explaining the
relation between genes/SNPs, mRNA expression and gene
methylation remains to be explored, and warrants further
detailed analyses.
Closing remarks
Undoubtedly, and regardless of forms of altered FD, fat deposition
is strongly determined by genetic factors. Whereas
specific forms of disturbed FD, such as lipodystrophies, can
be clearly assigned to individual genetic mutations, other
1282 Diabetologia (2014) 57:1276–1286
forms, such as visceral obesity, appear to be of a polygenic
nature and further influenced by environmental factors.
Although genes involved in the pathophysiology of monogenic
forms of altered FD may be attractive candidates in
studies aimed at investigating common genetic variation and
its effects on FD (as has been demonstrated for LMNAvariants
associated with type 2 diabetes and obesity), recent GWAS on
measures of FD proved to be the most efficient tool in identifying
genetic loci potentially harbouring genes controlling
FD (Fig. 1). The GWAS not only support the unique role of
developmental genes in the regulation of FD but also point to
numerous novel genes/loci whose yet unknown biological
role will be challenging researchers in the near future. Even
though it is unclear whether differential expression is a cause
or consequence of obesity/FD pattern, it might be postulated
that changes in gene/protein expression or in gene/protein
function caused by genetic variants may lead to variability in
FD profiles and thus link metabolic alterations to obesity
(Fig. 1). It is of note that many of the WHR-associated loci
have also shown associations in GWAS for metabolic traits
such as fasting glucose, insulin, adiponectin levels and BMI,
and with diseases such as type 2 diabetes, hypertension and
coronary heart disease (ESM Table 1), so further supporting
the suggestion that individuals genetically predisposed to
store fat in the visceral rather than the subcutaneous depot
are at higher risk of developing various metabolic complications.
The challenge is now to understand the biological
processes controlled by these genes leading to altered FD.
For example, considering the fact that dysfunctional adipose
tissue that is unable to expand through hyperplasia will lead to
visceral accumulation and ectopic fat deposition, it might be
hypothesised that some individuals with genetically determined
dysfunctional subcutaneous adipose tissue may be
more prone to storing variable amounts of fat in other ectopic
depots (e.g. liver, heart, muscle, or around large vessels)
depending on variation in other sets of genes (Fig. 3).
In conclusion, a better knowledge of the function of
FD genes will be crucial for understanding the complex
aetiology of obesity-related complications and might
even pave novel paths for treatment strategies for metabolic
disorders such as diabetes. A main focus of
future research is therefore to unravel the yet unknown
biological function of these novel ‘fat distribution
genes’. In addition, more accurate methods, including
cardiometabolic imaging, for assessment of FD will be
required to promote our knowledge in this field.
-Genetics
-Environment
a
Genetics
Genetics
-Genetics
-Environment
b
VIS/ectopic fat
SC fat
Hyperplasia Hyperplasia
Fig. 3 (a) Functional adipose tissue expansion through hyperplasia to
cover the need to store excess energy. (b) Dysfunctional adipose tissue
unable to expand through hyperplasia will lead to visceral adipose tissue
accumulation and to ectopic fat deposition. An excess in body fat arises in
most cases from a mixture of adverse lifestyle components (e.g. low
physical activity, hyper-energetic nutrition) and genetic susceptibility. In
addition, expansion capacity of subcutaneous adipose tissue and storage
of energy in various ectopic fat depots might be modulated by different
gene sets. Thus, some individuals with genetically determined dysfunctional
subcutaneous adipose tissue may be more prone to store variable
amounts of fat in other ectopic depots (e.g. liver, heart, muscle or around
large vessels) depending upon variation in other sets of genes. SC
subcutaneous; VIS visceral
Diabetologia (2014) 57:1276–1286 1283
Funding PK and MB are supported by a Collaborative Research Center
granted by the DFG (Sonderforschungsbereich 1052 ‘Mechanismen der
Adipositas’; B01, B03). YB is supported by a research grant from the
DFG (BO 3147/4-1). DS is funded by the Boehringer Ingelheim Foundation.
YB and PK are supported by the IFB AdiposityDiseases (K50D
and K7-45 to YB; K7-56 and K7-57 to PK). IFB AdiposityDiseases is
funded by the Federal Ministry of Education and Research (BMBF),
Germany, FKZ: 01EO1001.
Duality of interest The authors declare that there is no duality of
interest associated with this manuscript.
Contribution statement DS, YB, MB and PK were responsible for the
conception and design of the manuscript, drafting the manuscript, revising
it critically for intellectual content and approving the final version.
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