Transcript PowerPoint-presentation

HYPERTROPHIC OBESITY IS
ASSOCIATED WITH TYPE 2 DIABETES
AND IMPAIRED ADIPOGENESIS
Ulf Smith, MD, PhD
Professor of Internal Medicine, The Lundberg Laboratory for
Diabetes Research, Center of Excellence for Cardiovascular and
Metabolic Research, Sahlgrenska Academy, Göteborg University,
Göteborg, Sweden
Source: www.myhealthywaist.org
Features of the Metabolic Syndrome
Interleukin-6
Low-grade
inflammation
(
(
Type 2 diabetes
Prothrombotic
state
Hypertension
Dyslipidemia
Genetics +
lifestyle
Insulin resistance
Source: www.myhealthywaist.org
Cardiovascular
disease
Vicious Circle of Adipocyte Hypertrophy, Macrophage
Recruitment and Activation
Increased nutrient influx
Adipocytes
Preadipocytes
Adipose hypertrophy and
hyperplasia allow adipose
tissue to grow
Macrophages
Larger adipocytes secrete
macrophage-attracting
chemokines
Chemokines
Cytokines
Free fatty acids (FFA)
Increased FFA release by insulin
resistant adipocytes activates
macrophages
Source: www.myhealthywaist.org
Activated macrophages block
preadipocyte recruitment and worsen
insulin resistance in mature adipocytes,
increasing FFA release and
macrophage activation
Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49
Hypertrophic Obesity is
Associated With Local and
Systemic Inflammation and
Insulin Resistance
Source: www.myhealthywaist.org
Steps Leading from Positive Energy Balance to Type 2 Diabetes
Weight loss
Positive energy
balance
Increasing
adipose tissue
storage capacity
Failure in
adipose tissue
expansion
Oxidation of
lipids
Storing of excess
lipids in safe forms
Increased lipid
flux to nonadipose organs
Toxic lipid
accummulation in
non-adipose organs
Increasing beta cell
number or function
Beta cell
compensation
Beta cell
failure
Increased insulin
demand
Local
inflammation
Insulin
resistance
Hyperglycemia
Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49
Source: www.myhealthywaist.org
Adipose Morphology
A
1000
500
1000
500
0
0
0
200
20
40
60
80
100
Body fat mass (kg)
0
120
C
60
Frequency (%)
100
50
0
-500
50
100
Body fat mass (kg)
150
D
Hyperplasia
Men
Women Nonobese Obese
Hypertrophy
50
150
Count
B
1500
Fat cell volume (pl)
Fat cell volume (pl)
1500
-300
-100
100
300
Morphology value (pl)
500
40
30
20
10
0
Adapted from Arner E et al. Diabetes 2010;59:105-9
Source: www.myhealthywaist.org
Clinical Findings in Women With Adipose Hyperplasia or
Hypertrophy
Variables
Hyperplasia
(n=254)
Hypertrophy
(n=218)
p value
Age (years)
38 ± 10
40 ± 11
0.01
Waist (cm)
100 ± 22
105 ± 19
0.01
0.895 ± 0.085
0.924 ± 0.098
0.0005
32.5 ± 9.4
33.1 ± 8.1
0.37
5.2 ± 1.4
5.4 ± 1.0
0.12
Insulin (mU/l)
10.1 ± 7.8
13.0 ± 7.7
<0.0001
HOMA index*
0.25 ± 0.33
0.42 ± 0.29
<0.0001
4.9 ± 1.0
5.1 ± 1.1
0.033
1.40 ± 0.39
1.28 ± 0.36
0.001
Triglycerides (mmol/l)
1.2 ± 0.8
1.5 ± 0.8
0.002
Fat cell volume (pl)
555 ± 224
825 ± 209
<0.0001
Fat cell number (x1010)
7.9 ± 2.8
5.3 ± 1.7
<0.0001
Waist-to-hip ratio
Body mass index (kg/m2)
Glucose (mmol/l)
Cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Values are mean ± SD. Age was compared by unpaired t-test. Since it was slightly different between
groups, the remaining values were compared by analysis of covariance with age as cofactor.
* Log 10 transformed
Adapted from Arner E et al. Diabetes 2010;59:105-9
Source: www.myhealthywaist.org
Insulin Resistance, Obesity and the Dysregulated Adipose Tissue
 Hypertrophic (enlarged adipose cells) obesity is associated
with a dysregulated adipose tissue with reduced local and
systemic insulin sensitivity irrespective of amount of body fat.
 These include several markers of reduced cellular PPAR
activation (reduced APM, GLUT4, FABP4, etc. and
increased inflammation).
 Ability to recruit new subcutaneous fat cells in (hyperplastic)
obesity protects against the insulin-resistant obesity
phenotype (metabolic syndrome).
APM: adipocyte-specific secretory protein
FABP4: fatty acid binding protein 4
GLUT4: glucose transporter type 4
PPAR: peroxisome proliferator-activated receptor gamma
Source: www.myhealthywaist.org
Reduced IRS-1 in Adipocytes
BLOT: IRS-1
BLOT: IRS-1
anti-IRS-1
anti-IRS-1 (c-t)
← IRS-1
anti-IRS-1 (NH2-t)
← IRS-1
anti-p85
anti-IR
← p85
anti-p85
C
anti-syp
C
Type 2
diabetes
Type 2 Type 1
diabetes diabetes
anti-IR: insulin receptor antibody
anti-IRS-1: insulin receptor substrate-1 antibody
C: healthy control
IRS-1: insulin receptor substrate-1
Copyright (1997) National Academy of Sciences, U.S.A.
Proc Natl Acad Sci U S A 1997;94:4171-5
Source: www.myhealthywaist.org
Reduced GLUT4 in Adipocytes
BLOT: GLUT4
C
Type 2 diabetes
Type 1 diabetes
C: healthy control
GLUT4: glucose transporter type 4
From Smith U
Unpublished data
Source: www.myhealthywaist.org
Enlarged Abdominal Adipose Cells in Individuals With Low
IRS-1 Expression
Low IRS-1/
GLUT4
(n=20)
Normal IRS-1/
GLUT4
(n=52)
p value
Cell size (µg/cell)
0.55 ± 0.03
0.42 ± 0.02
<0.001
Body mass index (kg/m2)
25.8 ± 0.6
24.6 ± 0.4
NS
Waist-to-hip ratio
0.92 ± 0.02
0.84 ± 0.01
<0.001
Markers of impaired differentiation is ~4-times more
frequent in first-degree relatives vs. nongenetic predisposition
Question: Is impaired adipose cell differentiation with enlarged cells a
consequence of genetic predisposition for type 2 diabetes and associated
with insulin resistance?
GLUT4: glucose transporter type 4
IRS-1: insulin receptor substrate-1
Adapted from Carvalho E et al. FASEB J 2001;15:1101-3
and Jansson PA et al. FASEB J 2003;17:1434-40
Source: www.myhealthywaist.org
Comparison of Lean and Overweight Individuals With or Without a
Genetic Predisposition for Type 2 Diabetes or Overweight/Obesity
Lean individuals
Genetic predisposition
Type 2 diabetes
Measure
Age (years)
Waist circumference (cm)
BMI (kg/m2)
Body fat mass (kg)
Fat cell volume (pl)
Delta value (pl)
HOMA index
HDL cholesterol (mmol/l)
Apolipoprotein AI (mmol/l)
Apolipoprotein B (mmol/l)
Apo B/apo AI
Yes
(n=17)
Overweight or obesity
No
(n=65)
Yes
(n=56)
No
(n=26)
38 ± 2
82 ± 2(*)
33 ± 1
79 ± 1
35 ± 1
80 ± 1*
32 ± 1
77 ± 1
22.9 ± 0.4
19 ± 1
511 ± 45**
22.4 ± 0.2
18 ± 1
400 ± 19
22.7 ± 0.2
18 ± 1
431 ± 23
22.2 ± 0.3
17 ± 1
407 ± 30
64 ± 38**
1.62 ± 0.24*
1.39 ± 0.10*
-37 ± 18
1.17 ± 0.08
1.62 ± 0.05
-15 ± 21
1.26 ± 0.09
1.56 ± 0.07
-18 ± 28
1.26 ± 0.16
1.60 ± 0.07
1.37 ± 0.07
0.94 ± 0.06(*)
0.72 ± 0.07*
1.48 ± 0.05
0.82 ± 0.04
0.57 ± 0.03
1.43 ± 0.05
0.86 ± 0.04
0.63 ± 0.04
1.51 ± 0.07
0.84 ± 0.06
0.56 ± 0.04
Values are mean ± SE. Significances (by t-test) were only calculated between groups with heredity or not for
type 2 diabetes and between groups with heredity or not for overweight or obesity.
(*) 0.05<p<0.1, *p<0.05, **p=0.01
Adapted from Arner P et al. PLoS One 2011;6:e18284
Source: www.myhealthywaist.org
Adipocyte Hypertrophy, Fatty Liver and Metabolic Risk
Factors in South Asians: The Molecular Study of
Health and Risk in Ethnic Groups (mol-SHARE)
Sonia S. Anand, Mark A. Tarnopolsky, Shirya Rashid, Karleen M. Schulze,
Dipika Desai, Andrew Mente, Sandy Rao, Salim Yusuf, Hertzel C. Gerstein,
and Arya M. Sharma
Conclusions
South Asians have an increased adipocyte area compared to white Caucasians.
This difference accounts for the ethnic differences in insulin, HDL cholesterol,
adiponectin, and ectopic fat deposition in the liver.
Adapted from Anand SS et al. PLoS One 2011;6:e22112
Source: www.myhealthywaist.org
Influence of Adipose Tissue Characteristics on Ethnic
Differences in Adiponectin, Insulin and HDL cholesterol
South Asian
European
Adiponectin (µg/ml)
9
p=0.002
p=0.15
Fasting insulin-In (pmol/l)
p=0.006
8
4.5
7
4.0
6
3.5
5
N=108
N=79
Age + sex + BMI Age + sex + BMI +
adipocyte cell area
HDL cholesterol (mmol/l)
5.0
p=0.13
1.5
p=0.03
p=0.84
1.0
0.5
0.0
3.0
N=101
N=79
Age + sex + BMI Age + sex + BMI +
adipocyte cell area
N=108
N=79
Age + sex + BMI Age + sex + BMI +
adipocyte cell area
Adapted from Anand SS et al. PLoS One 2011;6:e22112
Source: www.myhealthywaist.org
Influence of Adipose Tissue Characteristics on Ethnic
Differences in Liver Fat
South Asian
European
14
12
Liver fat (%)
p=0.005
10
p=0.04
p=0.30
8
6
4
2
0
N=95
N=74
Age + sex + BMI
Age + sex + BMI +
adipocyte cell
area
N=55
Age + sex + BMI +
adipocyte cell area +
deep/superficial
fat ratio
Adapted from Anand SS et al. PLoS One 2011;6:e22112
Source: www.myhealthywaist.org
Lower Capacity of South Asians to Store Fat in Subcutaneous
Adipocytes Compared to White Caucasians
Visceral depot
Excess energy
No change in
cardiometabolic
factors
Superficial subcutaneous adipose tissue
Deep subcutaneous adipose tissue
Adipocyte hyperplasia
No liver fat
Abnormal response to chronic overnutrition (e.g. in South Asians vs. white Caucasians)
Visceral fat
Excess energy
Change in
cardiometabolic
factors:
Fatty acid flux
Superficial subcutaneous adipose tissue
Deep subcutaneous adipose tissue
Adipocyte hypertrophy
↓ Adiponectin
Source: www.myhealthywaist.org
Liver fat accumulation
↑ Insulin
↑ Glucose
↑ Triglycerides
↓ HDL cholesterol
↑ C-reactive protein
↑ Blood pressure
Adapted from Anand SS et al. PLoS One 2011;6:e22112
Summary
 Genetic predisposition for type 2 diabetes is associated
with a restricted adipogenesis and, thus, hypertrophic
obesity even in the absence of obesity (body mass index).
 Due to lack of precursor cells to undergo
adipogenesis?
(Diabetes 2009;58:1550-7)
 Or inadequate signalling/activation of adipogenesis?
Prime candidates:
 BMP4 induces committment of precursor cells into the
adipocyte lineage.
 Canonical Wnt prevents PPAR activation and
differentiation of preadipocytes.
BMP4: bone morphogenetic protein 4
PPAR: peroxisome proliferator-activated receptor gamma
Source: www.myhealthywaist.org
Canonical Wnt Signalling Regulates Mesenchymal Stem Cell Fate
Wnt +
Wnt +
Mesenchymal
stem cells
Myoblasts
Wnt -
+
Preadipocytes
Osteoblasts
BMP4: bone morphogenetic protein 4
C/EBPα: CCAAT/enhancer binding protein
alpha
C/EBPδ/β: CCAAT/enhancer ninding protein
delta/beta
PPAR: peroxisome proliferator-activated
receptor gamma
TNF-: tumor necrosis factor-alpha
BMP4
TNF-
+
Preadipocyte
genes
Adipogenic
stimuli
Wnt
β-catenin
C/EBPδ/β
PPARγ
C/EBPα
Adipocytes
Source: www.myhealthywaist.org
Adipocyte genes
Adapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
Local Factors Regulates Adipogenesis
A) Nutritional deprivation
Preadipocyte
Adipocyte
Adipogenesis
Adipocyte
hyperplasia
B) Overnutrition
Adipocyte
Preadipocyte
Adipogenesis
Ectopic lipid accumulation
(liver and muscle)
C) Chronic overnutrition
Hypertrophic
adipocytes
Preadipocyte
Adipose tissue inflammation
Adipogenesis
Source: www.myhealthywaist.org
Adapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
A Model for the Wnt Activation of the Beta-Catenin Signalling
Pathway With Wnt Signal
Wnt
LRP
Frizzled
Active
dishevelled
Axin
Inactive GSK-3β
Stable
β-catenin
APC
Unphosphorylated β-catenin
migrates to nucleus and
displaces groucho
Groucho
LEF-1/TCF
Transcription
From Smith U
Unpublished data
Source: www.myhealthywaist.org
Impaired Adipogenesis in Hypertrophic Obesity
140
Cell size (µm)
120
100
80
60
40
0
1
2
3
4
5
Oil Red O (fold change)
Adapted from Gustafson B & Smith U Diabetes 2012:61;1217-24
Source: www.myhealthywaist.org
Hypertrophic Obesity
 Is not due to lack of adipogenic precursor cells but to
inappropriate inhibitory signalling.
 BMP4 plays a role for precursor cell commitment and
differentiation.
 Wnt activation prevents the effect of BMP4 and is
inappropriately activated in hypertrophic obesity.
BMP4: bone morphogenetic protein 4
Source: www.myhealthywaist.org
Conclusions
1. Genetic predisposition for type 2 diabetes is
associated with a restricted adipogenesis and
hypertrophic obesity.
2. The restricted adipogenesis in hypertrophic
obesity is not due to lack of precursor cells but
to inadequate signalling/activation mainly
involving inadequate suppression of canonical
Wnt.
Source: www.myhealthywaist.org
Source: www.myhealthywaist.org