mechanisms driving adipose tissue mass growth - … · mechanisms driving adipose tissue mass...
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Mechanisms driving adipose tissue mass growth
-the role of fat cell size and local inflammation
Mikael Rydén M.D, Ph.D
Karolinska Institutet Dep of Medicine
Karolinska University Hospital, Huddinge Stockholm Sweden
Obesity development-the old view Once generated in childhood, fat cells are retained and alter in size according to weight changes Based on studies of fat cell size and number on prisoners before and after dietary induced weight change
Obesity development-the new view The growth of fat tissue is dependent on a constant renewal (adipogenesis) involving both cell growth (hypertrophy) and proliferation (hyperplasia)
Why?.....
14 C reading Cellular
age
Strategy to establish cellular age by measuring the nuclear bomb test derived 14C in DNA
Lipid filling
Cell death
Adipocyte turnover in adult humans •10% of the adipocyte pool turned-over each year •Rate of adipogenesis and cell death 2-fold increased in obesity
Lipid filling
Cell death
obese nonobese Spalding et al Nature 2008;453:783-7
0
1
2
3
4
5
6
7
8
9
0.5 3 9 15 35 55 60+
A g e
Fat c
ell n
umbe
r x
10
10
Constant fat cell number during ageing among adults
obese
lean Children data from Knittle et al JCI 63:239,1979
Spalding et al Nature 453:783,2008
Adipocyte turnover in adult humans Fat cell number is constant!
•Constant fat cell number throughout adult life Spalding et al Nature 2008;453:783-7 •What about weight loss?
Bariatric surgery Spalding et al Nature 2008;453:783-7
Cancer cachexia Rydén et al Cancer 2008 113:1695-704
Relationship between fat cell size and body fat
0
300
600
900
1200
1500
Fat
cel
l vou
me,
pl
0 20 40 60 80 100 120 140 Body fat, kg
Large fat cells associate with •Insulin resistance •Increased risk of developing type 2 diabetes
HOW CAN WE SEPARATE THE
EFFECT OF CELL SIZE
FROM THE EFFECT OF BODY FAT?
How can we estimate the impact of fat cell size? Algorithm to obtain body fat independent classification
0
300
600
900
1200
1500
Fat
cel
lvo
ume,
pl
0 20 40 60 80 100 120 140 Body fat, kg
Hypertrophy
Found-expected volume (+value) = degree of hypertrophy
Hyperplasia
Found-expected volume (-value) = degree of hyperplasia
E Arner et al Diabetes, 59: 17-25, 2010
”Morphology value”
Hypertrophy
Hyperplasia
0 5
10 15 20 25 30 35 40 45
BM
I
Obese 0
1
2
3
4
5
6
HO
MA
p<0.001
p<0.001
Lean
Insulin resistance Body mass index
Relationship between the morphology value and insulin sensitivity in 230 lean and 400 obese
Lean Obese
Obese
p<0.01
p=0.01
Lean
Insulin stimulated Basal (spontaneous)
Adipose cellularity in 90 lean and 310 obese Adipocyte lipogenesis
Lean Obese 0
1
2
3
4
Lip
ogen
esis
per
10
mill
ion
cells
0
2
4
6
8
10
12
Lip
ogen
esis
per
10
mill
ion
cells
NS NS
Hypertrophy
Hyperplasia
Noradrenaline-stimulated Basal (spontaneous)
Adipose cellularity in 220 lean and 300 obese women Adipocyte lipolysis
Lip
olys
is p
er 1
0 m
illio
n ce
lls
0
3
6
9
p<0.0001
p<0.0001
Lip
olys
is p
er 1
0 m
illio
n ce
lls
Lean Obese 0
3
6
9
12
Lean Obese
NS NS
Hypertrophy
Hyperplasia
HYPERPLASIA HYPERTROPHY
Fat cell size and number matters
•Risk to develop type 2 diabetes C Weyer et al Diabetologia 43: 1498-1506, 2000 M Lönn et al FASEB J. 24:326-31. 2010 •Strong heredity for type 2 diabetes P Arner et al PLoS One 6:e18284, 2011
Protective
Irrespective of whether you are lean or obese, your adipose tissue can be in two different ways
Much lipid filling
Cell death
Mechanisms causing different forms of morphology
Less lipid
filling
Cell death
SLOW TURNOVER
⇓ hypertrophy
RAPID TURNOVER ⇓
hyperplasia E Arner et al Diabetes, 59:105-9, 2010
WHAT KEEPS HUMAN ADIPOCYTE TURNOVER GOING?
The old view
0
200
400
600
800
Sec
retio
n pe
r tis
sue
w
ei g
ht
*
TNF-alpha IL-6 MCP-1
The inflamed adipose tissue among obese
Secretion of inflammatory proteins from human sc
adipose tissue
NONOBESE OBESE
Leucocyte infiltration in obese adipose tissue
GREEN = the leukocyte antigen CD45 BLUE = nuclear staining with DAPI
*
* * *
*
*
*
0
2 4
6 8
10 12
14
Lean Subc obesity
Visceral obesity
Subc Omental
Macrophages in human adipose tissue.
Percentage of all tissue cells
Adopted from Harman-Boehm et al, JCEM, 92:2240-47, 2006
Macrophage infiltration and TNFα secretion in adipose tissue obese and nonobese subjects
0
1
2
3
4
5
6
Lean n=25
Obese n=100
50%
TNFα secretion from sc adipose tissue
Rydén M et al, unpublished
Effects of TNFα on adipocytes
• Increases lipolysis • Decreases lipogenesis • Attenuates preadipocyte proliferation and
adipocyte differentiation • Increases adipocyte cell death
Reviewed in Rydén M and Arner P. J Intern Med. 200 Oct;262(4):431-8.
Are adipose inflammatory factors
just bad or have we
misunderstood them?
Adipokine secretion in relation to adipose cellularity in lean healthy women (BMI<25 kg/m2)
E Arner et al N Engl J Med, 362:1151-3, 2010 T
NF-
alph
a se
cret
ion
0
200
400
600
800
1000
1200
-400 -300 -200 -100 0 100 200
Adipose morphology, picolitres
r2 = 0.32 p = 0.005
0
100
200
300
400
500
600
-400 -300 -200 -100 0 100 200 Adipose morphology, picolitres
Il-6
sec
retio
n A
dipo
nect
in s
ecre
tion
0
100
200
300
400
-400 -300 -200 -100 0 100 200
Adipose morphology, picolitres
0
2
4
6
8
10
12
-400 -300 -200 -100 0 100 200
Adipose morphology, picolitres
Lep
tin s
ecre
tion
0
200
400
600
800
1000
1200
-0.1 0.2 0.5 0.8 1.1 1.4 1.7 2.0
TN
F-al
pha
secr
etio
n r2 = 0.43 p = 0.0018
0
200
400
600
800
1000
1200
0 0.5 1.0 1.5 2.0 2.5
TNF-alpha mRNA
r2 = 0.38 p = 0.005
TNF-alpha mRNA
TN
F-al
pha
secr
etio
n
Tissue Adipocytes
TNF-alpha secretion and gene expression in adipose tissue of
lean healthy women (BMI<25 kg/m2) E Arner et al N Engl J Med, 362:1151-3, 2010
Could TNFα play a physiological role?
• Inhibit adipocyte growth? • Limit fat cell proliferation and increase fat
cell death? • A response which becomes maladaptive in
an environment with constant caloric over-supply?
Upstream regulator(s) of human adipose
inflammation?
TF
TF TF
TF TF
TF
TF
TF
TF TF
MCP-1 TNF-α IL-1
A network of transcription factors is linked to inflammatory proteins in human fat cells
Twist-1 • In a gene expression profile on sc adipose tissue from lean and
obese twist1 expression was significantly lower in obese subjects (Dahlman I unpublished data)
• Basic helix-loop-helix transcription factor • Identified in Drosophila melanogaster • Binds to E-boxes with the CANNTG motif • Implicated in bone formation and tumor metastasis • Mutations associated with Saethre-Chotzen syndrome • Twist-1 and -2, 66% identity at aa-level • Twist2-/- and twist1+/- twist2+/- mice have increased levels of
TNFα,IL-6 and IL-1β (Šošić D et al. Cell 2003)
• Twist1 negatively regulates transcriptional activity of PGC-1α in murine BAT (Pan D et al. Cell 2009)
Relationship between Twist-1 gene expression and secretion of inflammatory proteins in human subcutaneous adipose tissue
A. B. IL
-6 s
ecre
tion/
cel
l
low twist-1
high twist-1
*
0 2 4 6 8
10 12 14
TNFα
sec
retio
n / c
ell
0 0.5
1 1.5
2 2.5
3 3.5
4
*
low twist-1
high twist-1
Petterson A et al, J Clin Endocrinol Metab, 96:133-41, 2010
0
100
200
300
400
Rel
ativ
e lu
cife
rase
act
ivity
(f
old
indu
ctiu
on)
pIL6 +pcDNA3.1
pIL6 +Twist1
*
Luciferase
-541 +68 pIL6
Twist1 regulates cytokine expression 3T3-L1 cells were transfected with Twist1 cDNA and a gene reporter
construct for IL-6 (pIL) or empty pcDNA3.1
Petterson A et al, Diabetes, 59:564-71, 2010
exon exon exon promotor
mRNA ⇓
Production of TNF-α, Il-6 and MCP-1
Interaction between Twist-1 and inflammation in human adipose tissue
Twist-1
Petterson A et al, Diabetes, 59:564-71, 2010
Reduced Twist1 potentiates the pro-inflammatory effect of TNFα
Petterson A et al, J Clin Endocrinol Metab, 96:133-41, 2010
Relationship between Twist-1 gene expression and the morphology of
human subcutaneous adipose tissue
Petterson A et al, J Clin Endocrinol Metab, 96:133-41, 2010
Hyperpl.
Hypertr.
Hyperpl.
Hypertr.
0
20
40
60
80
Twis
t1 m
RN
A (A
.U.)
Non-obese Obese
F= 21.3 p < 0.001
Glucose
Role of adipose inflammation in man
FFA
Mesenchymal stem cells
TNFα
Macrophages
MCP-1 TNFα
DIFFERENTIATION AND LIPID FILLING OF FAT CELLS
Lipids *
TNFα
Pre-adipocytes
TNFα
CELL DEATH
TNFα
hyperplasia hypertrophy
Protected
Adipose cellularity is clinically important for nonobese
Decreased insulin sensitivity
Type 2 diabetes risk
Alterations in transcription
factor regulation
SUMMARY The link between inflammation and adipogenesis
•There is a high turnover of fat cells in adult life although the total number of fat cells is constant
•Hypertrophic fat (few but large cells) is linked to development of insulin resistance irrespective of BMI
•Lean apparently healthy subjects with adipose hypertrophy have decreased insulin sensitivity
•Adipocyte turnover is an important determinant of adipose hypertrophy/hyperplasia, turnover (and thereby adipogenesis) and is high in hyperplasia
•Local inflammation may impact on morphology (hypertrophy/hyperplasia) of adipose tissue, hypertrophy is associated with inflammation
•Adipose inflammation is governed by a network of transcription factors
•Characterization of factors regulating turnover/morphology currently under way
LIPID LABORATORY •Peter Arner •Gaby Åström •Eva Sjölin •Kerstin Wåhlen •Clara Bambace •Amanda Petterson •Ingrid Dahlman •Britt-Marie Leijonhufvud •Katarina Hertel •Hans Wahrenberg •Elisabeth Dungner •Jurga Laurencikiene •Johan Hoffstedt •Patrik Löfgren •Daniel Andersson •Agne Kulyte •Silvia Lorente •Niklas Mejhert
•Erik Arner •Lennart Blomqvist •Kirsty Spalding •Pål Westermark •Samuel Bernard •Bruce Bucholz •Olaf Bergman •Tom Britton •Anneli Attersand •Pauline Decaunes •Anne Bouloumie •Carsten Daub •Karine Clement •Nicolas Veneteclef •Mats Eriksson
ADIPOCYTE TURNOVER WORKING FORCE EXTERNAL COLLABORATION
•Hernan Concha •Moustapha Hassan •Jonas Frisén •Erik Näslund •Per Heden •Claes Carnheim •Ian Cassady •David Hume •Shalender Bhasin •Karin Dahlman-Wright •Mireille Cormont •Jean-Francois Tanti •Erik van Nimwegen •Keith Frayn
Funded by 6:th and 7:th EU framework NUGENOB, Cost Action BM0602, ADAPT
Thank you for your attention!