Article

Dynamics of fat cell turnover in humans. Nature 453, 783-787

Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Nature (Impact Factor: 41.46). 07/2008; 453(7196):783-7. DOI: 10.1038/nature06902
Source: PubMed
ABSTRACT
Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.

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LETTERS
Dynamics of fat cell turnover in humans
Kirsty L. Spalding
1
, Erik Arner
1
,Pa
˚
l O. Westermark
2
, Samuel Bernard
3
, Bruce A. Buchholz
4
, Olaf Bergmann
1
,
Lennart Blomqvist
5
, Johan Hoffstedt
5
, Erik Na
¨
slund
6
, Tom Britton
7
, Hernan Concha
5
, Moustapha Hassan
5
,
Mikael Ryde
´
n
5
, Jonas Frise
´
n
1
& Peter Arner
5
Obesity is increasing in an epidemic manner in most countries and
constitutes a public health problem by enhancing the risk for
cardiovascular disease and metabolic disorders such as type 2 dia-
betes
1,2
. Owing to the increase in obesity, life expectancy may start
to decrease in developed countries for the first time in recent
history
3
. The factors determining fat mass in adult humans are
not fully understood, but increased lipid storage in already
developed fat cells (adipocytes) is thought to be most important
4,5
.
Here we show that adipocyte number is a major determinant for
the fat mass in adults. However, the number of fat cells stays
constant in adulthood in lean and obese individuals, even after
marked weight loss, indicating that the number of adipocytes is
set during childhood and adolescence. To establish the dynamics
within the stable population of adipocytes in adults, we have
measured adipocyte turnover by analysing the integration of
14
C derived from nuclear bomb tests in genomic DNA
6
.
Approximately 10% of fat cells are renewed annually at all adult
ages and levels of body mass index. Neither adipocyte death nor
generation rate is altered in early onset obesity, suggesting a tight
regulation of fat cell number in this condition during adulthood.
The high turnover of adipocytes establishes a new therapeutic
target for pharmacological intervention in obesity.
The fat mass can expand by increasing the average fat cell volume
and/or the number of adipocytes. Increased fat storage in fully dif-
ferentiated adipocyte s, resulting in enlarged fat cells, is well docu-
mented and is thought to be the most important mechanism whereby
fat depots increase in adults
4,5
. To analyse the contribution of the fat
cell volume in adipocytes to the size of the fat mass, we first analysed
the relationship between fat cell volume and total body fat mass
(directly measured with bioimpedance or estimated from body mass
index (BMI), sex and age in a large cohort of adults). As expected,
there was a positive correlation between the measures of fat mass and
fat cell volume both in subcutaneous fat (Fig. 1a–c), which represents
about 80% of all fat, and in visceral fat (Fig. 1d), which has a strong
link to metabolic complications of obesity. However, the relationship
between fat cell volume and fat mass markedly differed from a linear
relationship (likelihood ratio test P , 0.001, and Akaike information
criterion, described in Supplementary Information 1) in both sub-
cutaneous and visceral adipose regions and both sexes, indicating
that fat mass is determined by both adipocyte number and size. In
the nonlinear case, both fat cell number and fat cell size determine fat
mass. If the relationship had been linear, fat cell volume would be the
only important determinant of fat mass.
The generation of adipocytes is a major factor behind the growth of
adipose tissue during childhood
7
, but it is unknown whether the
number of adipocytes changes during adulthood. We assessed the
total adipocyte number in 687 adult individuals and combined this
data with previously reported results for children and adolescents
8
.
Although the total adipocyte number increased in childhood and
adolescence, this number levelled off and remained constant in adult-
hood in both lean and obese individuals (adults over 20 yr, grouped
in 5-yr bins; ANOVA, lean P 5 0.68, obese P 5 0.21; Fig. 2a and
Supplementary Information 3). Thus, the difference in adipocyte
number between lean and obese individuals is established during
childhood
7,8
and the total number of adipocytes for each weight
category stays constant during adulthood (Fig. 2b). The small vari-
ation in adipocyte number for each BMI category demonstrates that
this is a stable cell population during adulthood.
To analyse whether alterations in adipocyte number may contri-
bute to changed fat mass under extreme conditions, we next asked
whether fat cell number is reduced during major weight loss (mean
body weight loss, 18 6 11%, mean 6 s.d.) by radical reduction in
calorie intake by bariatric surgery (reduction of the stomach with
the purpose of facilitating weight loss). The surgical treatment
resulted in a significant decrease in BMI and fat cell volume; however,
this failed to reduce adipocyte cell number two years post surgery
(Fig. 2b, c and Supplementary Information 4), in line with previous
studies using different methodology
9–12
. Similar results were found in
a complementary longitudinal study
13
. Ref. 13 found that significant
weight gain (15–25%) over several months in non-obese adult men
resulted in a significant increase in body fat, which was accompanied
by an increase in adipocyte volume, but no change in adipocyte
number. Similar to our findings, subsequent weight loss back to
baseline resulted in a decrease of adipocyte volume, but, again, no
change in adipocyte number. Although we cannot rule out that a
more prolonged period of weight gain in adulthood could result in
an increase in adipocyte number, these results and ours indicate that
fat cell number is largely set by early adulthood and that changes in fat
mass in adulthood can mainly be attributed to change s in fat cell
volume. This may indicate that the number of adipocytes is set by
early adulthood with no subsequent cell turnover. Alternatively, the
generation of adipocytes may be balanced by adipocyte death, with
the total number being tightly regulated and constant.
We next set out to establish whether adipocytes are replaced dur-
ing adulthood, and, if so, at what rate. Adipocytes can be generated
from adult human mesenchymal stem cells and pre-adipocytes
in vitro
14
and may undergo apoptosis or necrosis
15–17
, but it is unclear
whether adipocytes are generated in vivo
14
. Cell turnover has been
difficult to study in humans. Methods used in experimental animals,
such as the incorporation of labelled nucleotides, cannot readily be
adapted for use in humans owing to potential toxicity. The detection
of cells expressing molecular markers of proliferation can give
1
Department of Cell and Molecular Biology, Karo linska Institute, SE-171 77 Stockholm, Sweden.
2
Institute for Theoretical Biology (ITB), Humboldt University Berlin and Charite
´
,
Invalidenstrasse 43, 10115 Berlin, Germany.
3
Institute of Applied and Computational Mathematics, Foundatio n of Research and Technology, 71110 Heraklion Crete, Greece.
4
Center for
Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, 7000 East Avenue, L-397, Livermore, California 94551, USA.
5
Department of Medicine, Karolinska
University Hospital, SE-141 86 Stockholm, Sweden.
6
Division of Surgery, Department of Clinical Science, Danderyds Hospital, Karolinska Institutet, SE-182 88 Stockholm, Sweden.
7
Department of Mathematics, Stockholm University, 106 91 Stockholm, Sweden.
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insights about mitotic activity, but fail to provide information
regarding the fate of the progeny of the dividing cells. This is a
limitation when studying postmitotic cell types, which do not divide
or express mitotic markers themselves (for example, neurons or
adipocytes) but may be replenished from proliferating stem or pro-
genitor cells, such as preadipocytes.
In this study, we used a recently developed method that is based on
the incorporation of
14
C from nuclear bomb tests into genomic DNA
and allows the analysis of cell turnover in humans
6,18
. Levels of
14
Cin
the atmosphere were relatively stable until the Cold War, when
above-ground nuclear bomb tests (1955–1963) caused a notable
increase
19,20
(Fig. 3a, b). Even though the detonations were conducted
at a limited number of locations, increased
14
C levels in the atmo-
sphere rapidly equalized around the globe. Since the Test-Ban Treaty
in 1963, the
14
C levels have dropped exponentially, not because of
radioactive decay (half-life 5,730 yr), but by diffusion from the atmo-
sphere
21
. Atmospheric
14
C reacts with oxygen to form CO
2
, which is
incorporated into plants by photosynthesis. By eating plants, and
animals that live off plants, the
14
C concentration in the human body
closely parallels that in the atmosphere at any given point in time
22–24
.
Because DNA is stable after a cell has gone through its last cell divi-
sion, the
14
C level in DNA serves as a date mark for when a cell was
born; this can be used to retrospectively birth-date cells in humans
6,18
.
To address whether adipocytes are generated from newborn cells
in adulthood, we isolated fat cells ($98% purity, Supplementary
Information 4) from adipose tissue collected during liposuction or
abdominal wall reconstruction from 35 adult lean or obese indivi-
duals. The pure isolation of adipocytes is important because non-
adipose cells are present in adipose tissue and these cell types may
have a different turnover rate (see Supplementary Information 4 for a
full discussion). Genomic DNA was extracted from the purified
adipocytes, and
14
C levels were measured by accelerator mass
spectrometry and related to atmospheric
14
C data (Fig. 3c, d and
Supplementary Information 4). We first analysed individuals born
a
0
2
4
6
8
10
0 102030405060
Adipocyte number
(×10
10
cells)
Age (yr)
b
1,000
Fat cell volume
(picolitres)
800
*
600
400
200
0
Before
bariatric surgery
After
bariatric surgery
c
10
Fat cell number (×10
10
)
8
6
4
2
0
Before
bariatric surgery
After
bariatric surger
y
Figure 2
|
Adipocyte number remains stable in adulthood, although
significant weight loss can result in a decrease in adipocyte volume.
Total
adipocyte number from 595 (n lean 5 253; n obese 5 342) adult individuals
(squares) was combined with previous results for children and adolescents
8
(circles; n lean 5 178; n obese 5 120). a, The adipocyte number increases in
childhood and adolescence, with the number levelling off and remaining
constant in adulthood in both lean (blue) and obese (pink) individuals.
b, c, Major weight loss by bariatric surgery results in a significant decrease in
cell volume (
b), however fails to reduce adipocyte cell number (c), 1–2 yr
post surgery (n 5 20). All error bars represent s.e.m.; asterisk, P , 0.0001.
0 20 40 60 80 100 120
0
200
400
600
800
1,000
1,200
1,400
Fat cell volume (picolitres)
a
0 20 40 60 80 100 120
0
200
400
600
800
1,000
1,200
1,400
b
0 20 40 60 80 100 120
0
200
400
600
800
1,000
1,200
1,400
c
Body fat mass (kg)
0 20 40 60 80 100 120
0
200
400
600
800
1,000
1,200
1,400
d
Figure 1
|
Fat mass is determined by both adipocyte number and size.
a
d, The relationship between fat mass and fat cell volume was curvilinear
across the range of body fat mass in female (
a) and male (b) subcutaneous fat
(n female 5 480; n male 5 190), in combined female and male subcutaneous
fat (
c; n female 5 357, n male 5 117), and in male and female visceral fat (d; n
female 5 84, n male 5 51). This demonstrates that both adipocyte number
and adipocyte size are determinates of body fat mass. In
a, b and d, body fat
mass was estimated from BMI using a previously described formula
(conversion formula is described in Supplementary Information 1 and 4); in
c, fat mass was determined using bioimpedance. Fat cell volume is given in
picolitres, where 10
212
litres 5 10
29
cm
3
.
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well before the period of nuclear bomb tests. This provides a high
sensitivity to detect the generation of cells born after the time of onset
of the nuclear bomb tests (1955), because
14
C levels above those
present before the Cold War can be detected even if only a small
(1%) proportion of cells in a population are renewed
6
. In all analysed
individuals born before 1955 (n 5 10), the
14
C levels were substan-
tially higher than the atmospheric levels before the nuclear bomb
tests, indicating that generation of adipocytes had taken place after
1955 (Fig. 3c, see Supplementary Information 2 for all
14
C measure-
ments and associated data). The individuals were 0–22 years old at
the onset of nuclear bomb tests, establishing that adipocytes are
generated during adolescence and in early adulthood. New adipo-
cytes may also be formed by differentiation of existing post-mitotic
pre-adipocytes; hence, DNA integration of
14
C provides a lower
bound to the generation of adipocytes.
Analysis of individuals born before the onset of the nuclear bomb
tests provides a high sensitivity to detect cell turnover, but alone does
not allow the establishment of the turnover rate because a certain
14
C
level can correspond to the rising or the falling part of the atmospheric
14
C curve. However, the integration of data from individuals born
before and after the period of nuclear bomb tests allows determination
of cell turnover as well as the relative contribution of cell death and cell
renewal to this process (see Supplementary Information 3). We there-
fore also analysed
14
C levels in adipocyte genomic DNA from indivi-
duals born after the period of nuclear bomb tests (n 5 25). In all of
these individuals, the
14
C levels corresponded to surprisingly contem-
porary time points (Fig. 3d and Supplementary Information 2), pro-
viding a first indication that there is continuous and substantial
turnover of adipocytes in adult humans.
We next calculated the dynamics of fat cell turnover using a simple
birth and death model (detailed in Supplementary Information 3).
The model’s assumptions allow the calculation of kinetic rates for
individual subjects. The death rate of adipocytes is approximately
8.4 6 6.2% per yr (median 6 average deviation) in the total fat pool
of the body. The distribution of death rates is skewed towards lower
values and is not the normal gaussian (Jarque–Bera test for normality,
P , 0.05); therefore, the median 6 average deviation is more inform-
ative than the mean 6 s.d.
25
. To test the reliability of the death-rate
estimates, we used three different scenarios concerning the generation
of adipocytes early in life, and confirmed that different estimates of the
death rates do not differ from the median (sign test, P . 0.3; see
Supplementary Information 3 for description of the scenarios). We
divided the data set into lean (BMI , 25 kg per m
2
) and obese
(BMI $ 30 kg per m
2
, all of which had early onset obesity, see
Supplementary Information 4) for analyses of the influence of obesity
on adipocyte death rate. No significant difference in adipocyte death
rate was seen across the different BMIs, with obese individuals having
a median adipocyte death rate of 9.5 6 5.1% (median 6 average devi-
ation) per yr, versus 8.2 6 5.3% (median 6 average deviation) per yr
for lean individuals (P 5 0.6 using the Kruskal–Wallis test, which tests
for equality of medians; Fig. 4a). We found no trend for an increase in
average cell number in subjects aged 20–70 yr using data presented in
Fig. 2b (n 5 650 and P 5 0.19 by linear regression analysis), arguing
that the adipocyte death rate per yr must be matched with a similar
birth rate. This translates into an adipocyte turnover rate similar for all
weight categories. We calculate a median turnover rate of 8.4 6 6.2%
(median 6 average deviation) per yr, with half of the adipocytes
replaced every 8.3 yr.
Calendar year
Calendar year
Calendar year
Calendar year
a b
dc
14
C (‰)
Fraction modern (F)
Fraction modern (F) Fraction modern (F)
1925 1935 1945 1955 1965 1975 1985 1995 2005
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
1925 1935 1945 1955 1965 1975 1985 1995 2005
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
1925 1935 1945 1955 1965 1975 1985 1995 2005
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
900
800
700
600
500
400
300
200
100
0
1500BC 1000BC 500BC 0 500 1000 1500 2000
Figure 3
|
Turnover of adipocytes in adulthood. a, b, The levels of
14
C in the
atmosphere have been relatively stable over long time periods, with the
exception of a large addition of
14
C in 1955–1963 as a result of nuclear bomb
tests
21
. The boxed region in a is shown in more detail in b.
14
C levels from
modern samples are by convention given in relation to a universal standard
and corrected for radioactive decay, giving the D
14
C value
30
. c, d, Adipocyte
age in adult human subjects born before (
c) and after (d) nuclear bomb tests
were analysed by determining the
14
C concentration in adipocyte genomic
DNA using accelerator mass spectrometry. The measured
14
C value is
related to the recorded atmospheric levels to establish at what time point
they corresponded. The year is plotted on the x axis, giving the birth date of
the cell population. Three representative individuals born at different times
before the onset of the bomb tests reveals the generation of adipocytes after
birth (
c). Analysis of the oldest individuals established that adipocytes are
born in adolescence and in adulthood (
c).
14
C levels analysed in people born
after the period of nuclear bomb tests showed continuous and substantial
turnover of adipocytes in adult humans (
d). The time of birth of the person is
indicated by a vertical line in each graph and the BMI is shown numerically
(
c, d). Error bars for the accelerator mass spectrometry readings are too
small to be visualized in this graph. Each dot represents one individual.
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Using the death-rate estimates and the fat cell numbers calculated
for individual subjects, absolute fat cell production was calculated.
Obese individuals were found to have a significantly greater number
of adipocytes added per year than lean individuals: (0.8 6 0.5) 3 10
10
cells per yr versus (0.3 6 0.2) 3 10
10
cells per yr (median 6 average
deviation; P , 0.01, ANOVA; Fig. 4b). Loss of fat cells is therefore
compensated by the production of new fat cells, which is twice as high
in obese subjects compared with lean subjects. The fact that the total
number of new adipocytes added each year is greater in obese com-
pared with lean individuals, yet the proportion of newborn adipo-
cytes added each year (the turnover) is the same for both groups,
argues that the difference in cell number between the lean and obese
adults occurs before adulthood. In support of this, we found no
significant difference in the average age of adipocytes in lean
9.9 6 3.5 yr (mean 6 s.d.) versus obese 9.7 6 4.0 yr (mean 6 s.d.)
individuals (Fig. 4c). No significant correlation between the age of
subjects and cell death or between the age of patients and adipocyte
generation was found (Supplementary Information 3), suggesting a
constant turnover rate throughout adult life.
If the number of adipocytes is set to a higher level in obese people
before adulthood, this could be because cell-number expansion
begins earlier (age of onset), because expansion is faster (growth
relative to the initial cell number (IC) at age of onset), or because
expansion ends later (age at 90% of adult cell number). We used
combined adipocyte number data (Fig. 2a) to see whether one or
more of these factors determine adipocyte number. Using our birth
and death model, we determined that age at onset of adipocyte num-
ber expansion is significantly earlier in obese (2.1 6 0.9 yr) than in
lean (5.7 6 0.8 yr) subjects; the relative increase in adipocyte number
is higher in obese (2.4 6 0.6 IC yr
–1
) than in lean (1.3 6 0.3 IC yr
–1
)
subjects, but end of expansion of adipocyte number is earlier in obese
(16.5 6 1.3 yr) than in lean (18.5 6 0.7 yr) subjects (all values are
predicted values 6 95% confidence interval, Supplementary Infor-
mation 3). Therefore, adult cell number is set earlier in obese subjects
and is not caused by a prolonged expansion period in adulthood.
We find that the number of adipocytes for lean and obese indivi-
duals is set during childhood and adolescence, and that adipocyte
numbers for these categories are subject to little variation during
adulthood. Even after significant weight loss in adulthood and
reduced adipocyte volume, the adipocyte number remains the same.
Although we show that the adipocyte number is static in adults, we
also demonstrate that there is remarkable turnover within this popu-
lation, indicating that adipocyte number is tightly controlled and not
influenced by the energy balance. Studies of previously obese indivi-
duals after weight loss show that their adipose tissue hypercellularity
is associated with leptin deficiency, which is likely to increase appetite
and to lower energy expenditure
26
. These factors promote lipid accu-
mulation in fat cells and weight gain towards the status before weight
loss. Thus, a tight regulation of adipocyte number, together with
mechanisms maintaining their energy balance, may contribute to
why obese individuals have difficulties maintaining weight loss.
It should be stressed that our conclusions on the rates of adipocyte
turnover (
14
C data) were obtained from studies on subjects with early
onset of obesity. We cannot rule out that those who gradually gain
significant weight over years in adulthood may initially increase their
adipocyte size until a threshold is reached and thereafter recruit new
fat cells from committed precursor cells or mesenchymal stem cells.
Most obese adults have been obese since childhood, with less than
10% of children with normal weight going on to develop adult
obesity
27
. By contrast, over three-quarters of obese children go on
to become obese adults
27
. Thus, understanding the dynamics of
adipocyte turnover in adults who have been obese since childhood
is of great importance, especially given the current trend for an
increase in childhood obesity.
The size of organs can be regulated by different mechanisms, and
the number of cells in some tissues is controlled by a systemic feed-
back mechanism
28
. This is best understood for skeletal muscle, in
which growth and differentiation factor 8 (GDF8), also known as
myostatin, is secreted from myocytes and negatively regulates the
generation of new muscle cells and thereby sets the number of cells
29
.
Loss-of-function mutations in GDF8 result in a large increase in the
number (and size) of myocytes in animals and humans
29
. The steady
production of adipocytes in adults results in a stable size of the con-
stantly turning over adipocyte population. Feedback mechanisms
that control adipocyte turnover will be important to identify at a
molecular level because this may offer a novel target for pharmaco-
logical therapy when obesity is established and for other types of
intervention during childhood and adolescence when the final num-
ber of fat cells in the body is being set.
METHODS SUMMARY
Subjects. The relationship between subcutaneous or visceral fat cell volume,
BMI and fat mass was studied in two separate cohorts, and fat cell turnover
was studied in a third cohort, all of which are described in Supplementary
Information 4.
Isolated fat cells. Fat cells were isolated from the adipose tissue as described in
Supplementary Information 4. Details on how to measure weight, volume and
the number of fat cells as well as determination of the purity of the adipocytes are
given in Supplementary Information 4.
14
C analysis. Genomic DNA was prepared from isolated fat cells, and was puri-
fied and subjected to accelerator mass spectrometry analyses, as described in
Supplementary Information 4 and tabled in Supplementary Information 2.
Data analysis. The calculations of relationship between fat cell volume and BMI
or fat mass are described in detail in Supplementary Information 1. The calcula-
tions of fat cell death and generation are described in detail in Supplementary
Information 3.
Received 30 November 2007; accepted 7 March 2008.
Published online 4 May 2008.
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a
0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Lean Obese
Death rate (per yr)
b
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Lean Obese
Production rate
(×10
10
cells per yr)
*
c
8.0
8.5
9.0
9.5
10.0
10.5
Lean Obese
Adipocyte age (yr)
Figure 4
|
Effect of obesity on adipocyte generation and death. a,No
significant difference in adipocyte death rate per year was seen across the
different BMIs.
b, Obese individuals had a significantly greater number of
adipocytes added per year than lean individuals.
c, No significant difference in
the average age of adipocytes in lean versus obese individuals was found. In
a and b, values are the medians and error bars indicate the location of the first
and third quartiles; in
c, data are shown as mean 6 s.e.m. Asterisk, P , 0.01
for lean (n 5 13) versus obese (n 5 14) individuals, Kruskal–Wallis test.
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Supplementary Information is linked to the online version of the paper at
www.nature.com/nature.
Acknowledgements We thank M. Stahlberg and T. Bergman for help with
high-performance liquid chromatography (HPLC), D. Kurdyla, P. Zermeno and
A. Williams for producing graphite, and S. Zdunek for comments on the statistics
and modelling. This study was supported by grants from Knut och Alice
Wallenbergs Stiftelse, the Human Frontiers Science Program, the Swedish
Research Council, the Swedish Cancer Society, the Swedish Heart and Lung
foundation, the Novo Nordic Foundation, the Swedish Diabetes Foundation, the
Foundation for Strategic Research, the Karolinska Institute, the Tobias Foundation,
AFA Life Insurance Health Foundation and NIH/NCRR (RR13461). This work was
performed in part under the auspices of the US Department of Energy by University
of California, Lawrence Livermore National Laboratory under contract
W-7405-Eng-48.
Author Contributions K.L.S., P.A. and J.F. designed the study and wrote the
manuscript. E.A., P.O.W., S.B., O.B. and T.B. were responsible for the modelling and
statistics. K.L.S. and B.A.B. performed sample preparation and
14
C accelerator
mass spectrometry measurements. L.B., J.H. and E.N. collected clinical material.
H.C., M.H. and M.R. performed studies on fat cell purity.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to K.L.S. (kirsty.spalding@ki.se), J.F. (jonas.frisen@ki.se) or P.A.
(peter.arner@ki.se).
NATURE
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    • "The rate of this process is intermediate between epithelial cells and myocytes. In young adult mice, ?10%–15% of adipocytes are replaced every month (Rigamonti et al., 2011; Tang et al., 2011), and retrospective human studies also indicate a high turnover rate (Spalding et al., 2008). Under homeostatic conditions, the process is relatively constant, but it is sensitive to pharmacologic, physiologic, and dietary stimuli. "
    [Show abstract] [Hide abstract] ABSTRACT: Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · May 2015 · Journal of Molecular and Cellular Cardiology
  • Source
    • "Adipose-derived hormones and cytokines directly modulate systemic insulin sensitivity (Qatanani and Lazar, 2007). WAT expands by an increase in adipocyte number (hyperplasia ) and size (hypertrophy) (Spalding et al., 2008; Tchoukalova et al., 2010). Adipocytes derive from mesenchymal stem cells (MSCs) and preadipocytes that reside in the stromovascular fraction of WAT. "
    [Show abstract] [Hide abstract] ABSTRACT: Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell Metabolism
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    • "In isolated adipocytes, we do not find significant fat depotrelated differences in TL supporting the notion that the number of adipocytes remains largely constant during adulthood [6]. Higher preadipocyte proliferation rate in SAT compared to VAT may not be reflected by different TL in mature adipocytes due to the relatively low renewal rate of adipocytes [6]. One limitation of our study is that we can only evaluate TL at a given time point and can therefore not exclude that differences in the dynamic of adipocyte turn over exist between different fat depots. "
    [Show abstract] [Hide abstract] ABSTRACT: Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal subcutaneous AT (SAT), and (3) adipocytes and cells of the stromal vascular fraction (SVF). We further asked whether AT TL is related to age, anthropometric and metabolic traits. TL was analyzed by quantitative PCR in total human genomic DNA isolated from paired subcutaneous and visceral AT of 47 lean and 50 obese individuals. In subgroups, we analyzed TL in isolated small and large adipocytes and SVF cells. We find significantly shorter TL in subcutaneous compared to visceral AT (p<0.001) which is consistent in men and subgroups of lean and obese, and individuals with or without type 2 diabetes (T2D). Shorter TL in SAT is entirely due to shorter TL in the SVF compared to visceral AT (p<0.01). SAT TL is most strongly correlated with age (r=-0.205, p<0.05) and independently of age with HbA1c (r=-0.5, p<0.05). We found significant TL differences between superficial SAT of lean and obese as well as between individuals with our without T2D, but not between the two layers of SAT. Our data indicate that fat depot differences in TL mainly reflect shorter TL of SVF cells. In addition, we found an age and BMI-independent relationship between shorter TL and HbA1c suggesting that chronic hyperglycemia may impair the regenerative capacity of AT more strongly than obesity alone. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Biochemical and Biophysical Research Communications
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