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, PhDProfessor of Internal Medicine, The Lundberg Laboratory for

Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Sahlgrenska Academy, Göteborg University,

Göteborg, Sweden

http://www.myhealthywaist.org/


Source: www.myhealthywaist.orgSource: www.myhealthywaist.org

Features of the Metabolic Syndrome

Low-grade inflammation Prothrombotic

state

Dyslipidemia Hypertension

Type 2 diabetesCardiovascular

disease

Genetics +lifestyle

Interleukin-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




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

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

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lum

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l)

Body fat mass (kg)

B

120 0 50 100 150

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150

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Co

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Morphology value (pl)

C

-500 -300 -100 100 300 500

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60

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Fre

qu

ency

(%

)

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 4GLUT4: glucose transporter type 4PPAR: 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 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




C Type 2 diabetes Type 1 diabetes

BLOT: GLUT4

Reduced GLUT4 in Adipocytes

C: healthy controlGLUT4: glucose transporter type 4

From Smith UUnpublished 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

GLUT4: glucose transporter type 4IRS-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


N=108 N=79

9

8

7

6

5

p=0.002 p=0.15

Adiponectin (µg/ml)


Influence of Adipose Tissue Characteristics on Ethnic Differences in Adiponectin, Insulin and HDL cholesterol




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




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 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

+

PPARγ

C/EBPα

C/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-

+



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



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




Impaired Adipogenesis in Hypertrophic Obesity

Adapted from Gustafson B & Smith U Diabetes 2012:61;1217-24

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m)

Oil Red O (fold change)

0 1 2 3 4

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40

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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




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

Health & Medicine

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