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Source: www.myhealthywaist.org
HYPERTROPHIC OBESITY IS ASSOCIATED WITH TYPE 2 DIABETES
AND IMPAIRED ADIPOGENESIS
Ulf Smith, MD, PhDProfessor 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 inflammationLow-grade
inflammation Prothrombotic state
Prothrombotic state
DyslipidemiaDyslipidemia HypertensionHypertension
Type 2 diabetesType 2 diabetes Cardiovasculardisease
Cardiovasculardisease
Genetics +lifestyle
Genetics +lifestyle
Interleukin-6Interleukin-6
Insulin resistance
((((
Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgAdapted 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
Source: www.myhealthywaist.org
Hypertrophic Obesity is Associated With Local and Systemic Inflammation and
Insulin Resistance
Source: www.myhealthywaist.org
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
Source: www.myhealthywaist.org
Hyperplasia Hypertrophy
1500
1000
500
0
Fat
cel
l vo
lum
e (p
l)
Body fat mass (kg)
A
0 20 40 60 80 100
1500
1000
500
0
Fat
cel
l vo
lum
e (p
l)
Body fat mass (kg)
B
120 0 50 100 150
200
150
50
0
Co
un
t
Morphology value (pl)
C
-500 -300 -100 100 300 500
100
60
20
10
0
Fre
qu
ency
(%
)
D
Men Women Nonobese Obese
50
40
30
Adapted from Arner E et al. Diabetes 2010;59:105-9
Adipose Morphology
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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.
VariablesHyperplasia
(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
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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 4GLUT4: glucose transporter type 4PPAR: peroxisome proliferator-activated receptor gamma
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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 2diabetes
Type 1diabetes
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 antibodyanti-IRS-1: insulin receptor substrate-1 antibodyC: healthy controlIRS-1: insulin receptor substrate-1
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
C Type 2 diabetes Type 1 diabetes
BLOT: GLUT4
Reduced GLUT4 in Adipocytes
C: healthy controlGLUT4: glucose transporter type 4
From Smith UUnpublished data
Source: www.myhealthywaist.org
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
GLUT4: glucose transporter type 4IRS-1: insulin receptor substrate-1
Enlarged Abdominal Adipose Cells in Individuals With Low IRS-1 Expression
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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
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
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
Age + sex + BMI Age + sex + BMI +adipocyte cell area
N=108 N=79
9
8
7
6
5
p=0.002 p=0.15
Adiponectin (µg/ml)
Age + sex + BMI Age + sex + BMI +adipocyte cell area
Influence of Adipose Tissue Characteristics on Ethnic Differences in Adiponectin, Insulin and HDL cholesterol
Source: www.myhealthywaist.org
Adapted from Anand SS et al. PLoS One 2011;6:e22112
European
South Asian
Liv
er f
at (
%)
Age + sex + BMI Age + sex + BMI +adipocyte cell
area
N=95 N=74
Age + sex + BMI +adipocyte cell area +
deep/superficial fat ratio
N=55
p=0.005
p=0.04p=0.30
14
12
10
8
6
4
2
0
Influence of Adipose Tissue Characteristics on Ethnic Differences in Liver Fat
Source: www.myhealthywaist.org
Adapted from Anand SS et al. PLoS One 2011;6:e22112
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
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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 4PPAR: peroxisome proliferator-activated receptor gamma
Source: www.myhealthywaist.orgAdapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
Mesenchymal stem cells
Myoblasts Osteoblasts
Adipocytes
Preadipocytes
BMP4
Wnt + Wnt +
Wnt -
Wntβ-catenin
+
PPARγPPARγ
C/EBPαC/EBPα
C/EBPδ/βC/EBPδ/β
Adipocyte genes
Preadipocytegenes
Adipogenicstimuli
BMP4: bone morphogenetic protein 4C/EBPα: CCAAT/enhancer binding protein
alphaC/EBPδ/β: CCAAT/enhancer ninding protein
delta/betaPPAR: peroxisome proliferator-activated
receptor gammaTNF-: tumor necrosis factor-alpha
Canonical Wnt Signalling Regulates Mesenchymal Stem Cell Fate
TNF-
+
Source: www.myhealthywaist.org
A) Nutritional deprivation
AdipocytePreadipocyte
Adipogenesis
B) Overnutrition
AdipocytePreadipocyte
Adipogenesis
Adipocytehyperplasia
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
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
A Model for the Wnt Activation of the Beta-Catenin Signalling Pathway With Wnt Signal
LRP Frizzled
Axin
Activedishevelled
APC
Inactive GSK-3β
Stable β-catenin
Unphosphorylated β-cateninmigrates to nucleus anddisplaces groucho
Groucho
TranscriptionLEF-1/TCF
Wnt
From Smith U
Unpublished data
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Impaired Adipogenesis in Hypertrophic Obesity
Adapted from Gustafson B & Smith U Diabetes 2012:61;1217-24
140
120
100
80
Cel
l siz
e (µ
m)
Oil Red O (fold change)
0 1 2 3 4
60
40
5
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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
BMP4: bone morphogenetic protein 4
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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
Source: www.myhealthywaist.org