Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis

Source: www.myhealthywaist.org
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.orgSource: www.myhealthywaist.org
Features of the Metabolic Syndrome
Low-grade
inflammation Prothrombotic
state
Dyslipidemia Hypertension
Type 2 diabetes
Cardiovascular
disease
Genetics +
lifestyle
Interleukin-6
Insulin resistance
(
(

Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49
Macrophages
Preadipocytes
Adipocytes
Increased nutrient influx
Adipose hypertrophy and
hyperplasia allow adipose
tissue to grow
Larger adipocytes secrete
macrophage-attracting
chemokines
Increased FFA release by insulin
resistant adipocytes activates
macrophages
Chemokines
Free fatty acids (FFA)
Cytokines
Activated macrophages block
preadipocyte recruitment and worsen
insulin resistance in mature adipocytes,
increasing FFA release and
macrophage activation
Vicious Circle of Adipocyte Hypertrophy, Macrophage
Recruitment and Activation

Hypertrophic Obesity is
Associated With Local and
Systemic Inflammation and
Insulin Resistance

Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49
Weight loss Increasing
adipose tissue
storage capacity
Oxidation of
lipids
Storing of excess
lipids in safe forms
Increasing beta cell
number or function
Positive energy
balance
Failure in
adipose tissue
expansion
Increased lipid
flux to non-
adipose organs
Toxic lipid
accummulation in
non-adipose organs
Beta cell
compensation
Local
inflammation
Insulin
resistance
Increased insulin
demand
Beta cell
failure
Hyperglycemia
Steps Leading from Positive Energy Balance to Type 2 Diabetes

Hyperplasia Hypertrophy
1500
1000
500
0
Fatcellvolume(pl)
Body fat mass (kg)
A
0 20 40 60 80 100
1500
1000
500
0
Fatcellvolume(pl)
Body fat mass (kg)
B
120 0 50 100 150
200
150
50
0
Count
Morphology value (pl)
C
-500 -300 -100 100 300 500
100
60
20
10
0
Frequency(%)
D
Men Women Nonobese Obese
50
40
30
Adapted from Arner E et al. Diabetes 2010;59:105-9
Adipose Morphology

Clinical Findings in Women With Adipose Hyperplasia or
Hypertrophy
Adapted from Arner E et al. Diabetes 2010;59:105-9
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.
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
Waist-to-hip ratio 0.895 ± 0.085 0.924 ± 0.098 0.0005
Body mass index (kg/m2) 32.5 ± 9.4 33.1 ± 8.1 0.37
Glucose (mmol/l) 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
Cholesterol (mmol/l) 4.9 ± 1.0 5.1 ± 1.1 0.033
HDL cholesterol (mmol/l) 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
* Log 10 transformed

 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).
Insulin Resistance, Obesity and the Dysregulated Adipose Tissue
APM: adipocyte-specific secretory protein
FABP4: fatty acid binding protein 4
GLUT4: glucose transporter type 4
PPAR: peroxisome proliferator-activated receptor gamma

Reduced IRS-1 in Adipocytes
Copyright (1997) National Academy of Sciences, U.S.A.
Proc Natl Acad Sci U S A 1997;94:4171-5
anti-IRS-1
anti-p85
anti-IR
anti-syp
C Type 2
diabetes
Type 1
diabetes
BLOT: IRS-1 BLOT: IRS-1
anti-IRS-1 (c-t)
anti-IRS-1 (NH2-t)
anti-p85
C Type 2
diabetes
← IRS-1
← IRS-1
← p85
anti-IR: insulin receptor antibody
anti-IRS-1: insulin receptor substrate-1 antibody
C: healthy control
IRS-1: insulin receptor substrate-1

C Type 2 diabetes Type 1 diabetes
BLOT: GLUT4
Reduced GLUT4 in Adipocytes
C: healthy control
From Smith U
Unpublished data

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?
Adapted from Carvalho E et al. FASEB J 2001;15:1101-3
and Jansson PA et al. FASEB J 2003;17:1434-40
IRS-1: insulin receptor substrate-1
Enlarged Abdominal Adipose Cells in Individuals With Low
IRS-1 Expression

Lean individuals
Genetic predisposition
Type 2 diabetes Overweight or obesity
Measure
Yes
(n=17)
No
(n=65)
Yes
(n=56)
No
(n=26)
Age (years) 38 ± 2 33 ± 1 35 ± 1 32 ± 1
Waist circumference (cm) 82 ± 2(*) 79 ± 1 80 ± 1* 77 ± 1
BMI (kg/m2) 22.9 ± 0.4 22.4 ± 0.2 22.7 ± 0.2 22.2 ± 0.3
Body fat mass (kg) 19 ± 1 18 ± 1 18 ± 1 17 ± 1
Fat cell volume (pl) 511 ± 45** 400 ± 19 431 ± 23 407 ± 30
Delta value (pl) 64 ± 38** -37 ± 18 -15 ± 21 -18 ± 28
HOMA index 1.62 ± 0.24* 1.17 ± 0.08 1.26 ± 0.09 1.26 ± 0.16
HDL cholesterol (mmol/l) 1.39 ± 0.10* 1.62 ± 0.05 1.56 ± 0.07 1.60 ± 0.07
Apolipoprotein AI (mmol/l) 1.37 ± 0.07 1.48 ± 0.05 1.43 ± 0.05 1.51 ± 0.07
Apolipoprotein B (mmol/l) 0.94 ± 0.06(*) 0.82 ± 0.04 0.86 ± 0.04 0.84 ± 0.06
Apo B/apo AI 0.72 ± 0.07* 0.57 ± 0.03 0.63 ± 0.04 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
Comparison of Lean and Overweight Individuals With or Without a
Genetic Predisposition for Type 2 Diabetes or Overweight/Obesity
Adapted from Arner P et al. PLoS One 2011;6:e18284

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

N=108 N=79
1.5
1.0
0.5
0.0
p=0.03 p=0.84
Age + sex + BMI Age + sex + BMI +
adipocyte cell area
HDL cholesterol (mmol/l)
European
South Asian
5.0
4.5
4.0
3.5
3.0
p=0.006 p=0.13
Fasting insulin-In (pmol/l)
N=101 N=79
adipocyte cell area
N=108 N=79
9
8
7
6
5
p=0.002 p=0.15
Adiponectin (µg/ml)
adipocyte cell area
Influence of Adipose Tissue Characteristics on Ethnic
Differences in Adiponectin, Insulin and HDL cholesterol

European
South Asian
Liverfat(%)
adipocyte cell
area
N=95 N=74
Age + sex + BMI +
adipocyte cell area +
deep/superficial
fat ratio
N=55
p=0.005
p=0.04
p=0.30
14
12
10
8
6
4
2
0
Influence of Adipose Tissue Characteristics on Ethnic
Differences in Liver Fat

Superficial subcutaneous adipose tissue Deep subcutaneous adipose tissue
Excess energy
Visceral depot
Adipocyte hyperplasia
Excess energy
Visceral fat
Adipocyte hypertrophy
↓ Adiponectin
Fatty acid flux
No liver fat
Liver fat accumulation
Abnormal response to chronic overnutrition (e.g. in South Asians vs. white Caucasians)
No change in
cardiometabolic
factors
Change in
cardiometabolic
factors:
↑ Insulin
↑ Glucose
↑ Triglycerides
↓ HDL cholesterol
↑ C-reactive protein
↑ Blood pressure
Lower Capacity of South Asians to Store Fat in Subcutaneous
Adipocytes Compared to White Caucasians
Superficial subcutaneous adipose tissue
Deep subcutaneous adipose tissue

 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.
Summary
BMP4: bone morphogenetic protein 4
PPAR: peroxisome proliferator-activated receptor gamma

Adapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
Mesenchymal
stem cells
Myoblasts Osteoblasts
Adipocytes
Preadipocytes
BMP4
Wnt + Wnt +
Wnt -
Wnt
β-catenin
+
PPARγ
C/EBPα
C/EBPδ/β
Adipocyte genes
Preadipocyte
genes
Adipogenic
stimuli
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
Canonical Wnt Signalling Regulates Mesenchymal Stem Cell Fate
TNF-
+

A) Nutritional deprivation
AdipocytePreadipocyte
Adipogenesis
B) Overnutrition
AdipocytePreadipocyte
Adipogenesis
Adipocyte
hyperplasia
C) Chronic overnutrition
Hypertrophic
adipocytes
Preadipocyte
Adipogenesis
Ectopic lipid accumulation
(liver and muscle)
Adipose tissue inflammation
Local Factors Regulates Adipogenesis
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
LRP Frizzled
Axin
Active
dishevelled
APC
Inactive GSK-3β
Stable
β-catenin
Unphosphorylated β-catenin
migrates to nucleus and
displaces groucho
Groucho
TranscriptionLEF-1/TCF
Wnt
From Smith U
Unpublished data

Impaired Adipogenesis in Hypertrophic Obesity
Adapted from Gustafson B & Smith U Diabetes 2012:61;1217-24
140
120
100
80
Cellsize(µm)
Oil Red O (fold change)
0 1 2 3 4
60
40
5

 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.
Hypertrophic Obesity

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.
Conclusions

Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis

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