Presentation copyright © 2011 David A Bender
Obesity leads to metabolic syndrome leads to diabetes
David A Bender
Emeritus Professor of Nutritional Biochemistry
University College London
d.bender@ucl.ac.uk
http://www.david-bender.purplecloud.net
for treatment that works
http://www.healthwatch-uk.org
Obesity
Daniel Lambert, 1770-1809
weight 330 kg (52st 11lb)
painted by Benjamin Marshall, Leicestershire Museum and Art Gallery postcard
Body weight and (premature) mortality
American Cancer Society Study: 750,000 people followed for 15 years
(Lew & Garfinkel, 1979)
relative mortality
2
1.8
1.6
1.4
1.2
1
0.8
<80
8089
9099
100- 110- 120- 130- >140
109 119 129 139
% average body weight
Body Mass Index = weight (kg) / height2 (m)
BMI 20 - 25
desirable range
BMI 25 - 30
overweight
BMI 30 - 40
obesity
BMI > 40
severe obesity
Body Mass Index = weight (kg) / height2 (m)
Obesity
Michelangelo’s David is to return to Italy after 2 years on loan to the USA
Percent of UK population overweight or obese
1980
60
50
39
40
32
30
20
6
10
8
0
BMI>25
BMI>30
men
60
1991
53
women
44
50
40
30
20
13
16
10
Health of the Nation target
to halve obesity within a decade
UK Department of Health data
BMI>25
0
BMI>30
men
women
Percent of UK population obese (BMI >30)
percent obese
25
20
15
10
5
0
1980 1987
1993 1994
1995 1996
1997 1998
1999 2000
2001
Health of the Nation target
to halve obesity within a decade
UK Department of Health data, Chief Medical Officer’s report, 2002
women
men
Overweight and obesity in UK
men
70
67
63
60
53
50
45
39
40
30
20
10
6
8
13
17
24
0
1980
BMI >25
1987
1991
1998
BMI >30
2003
women
70
60
60
53
50
44
40
36
32
30
20
10
8
12
16
21
26
0
1980
BMI >25
1987
1991
1998
BMI >30
2003
USA – meals outside home
percent of food spending
40
40
35
percent of calories consumed
30
30
38
25
40
20
35
15
30
10
25
5
18
20
0
1977
1996
Food is cheaper
 higher in fat (especially saturated fat)
 higher in high fructose syrups
15
10
5
0
1977
1996
Critser, G. (2003) Fatland – how Americans became the fattest people in the world, Penguin Books, London
Average and desirable physical activity
Average PAL in UK (occupational + leisure) = 1.4
Desirable PAL for fitness = 1.7
In UK this is achieved by:
22% of men
13% of women
The distribution of fat is important
Abdominal obesity – the male pattern
Hip-thigh obesity – the female pattern
The distribution of fat is important
CT scan of the abdomen in an obese female; black areas show fat
Visceral (abdominal) fat
Subcutaneous fat
Source: Wilkin TJ, Ch 4 in Adult obesity: a paediatric challenge, Voss LD & Willkin TJ, Eds, Taylor & Francis, 2003
The distribution of fat is important
Sex difference in mortality from cardiovascular disease
ratio men : women
3.5
3
2.5
raw data
2
1.5
1
0.5
0
Larsson et al, 1992
corrected for BMI, bp and
cholesterol
corrected for waist:hip ratio
The distribution of fat is important
% diabetic
Diabetes with obesity and waist : hip ratio – women
20
15
10
5
0
>150% ideal wt
121-150% ideal wt
<121% ideal wt
<0.73 <0.76 <0.8
waist : hip ratio
Hartz et al, 1984
>0.8
Insulin resistance – the metabolic syndrome
insulin resistance
dyslipidaemia (elevated triacylglycerol, low HDL)
hypertension (high blood pressure)
abdominal obesity
polycystic ovary syndrome
hyperuricaemia and gout
Diagnosed by 3 or more of:
Abdominal obesity
waist circumference > 102cm (men) or 88 cm (women)
Hypertriglyceridaemia
> 150 mg /dL
Low HDL cholesterol
< 1 mmol /L (men) or < 1.3 mmol /L (women)
High blood pressure
> 130 / 85 mm Hg
Fasting hyperglycaemia
> 6.2 mmol /L
Increased risk of atherosclerosis and cardiovascular disease
Globally 239 million people affected in 2010
The adipocyte before 1994
insulin receptor
expression of
lipoprotein lipase
fatty acid and
triacylglycerol synthesis
nefa + glycerol
LPL
chylomicron
and VLDL
triacylglycerol
triacylglycerol synthesis
activation of hormone-sensitive lipase
fatty acids
White adipose tissue
adrenaline receptor
The ob/ob obese mouse
 Hyperphagic
 but obese even when pair-fed
 Poor cold adaptation
The ob/ob obese mouse
Hypothesis
A defect in non-shivering thermogenesis
(facultative uncoupling of electron transport in mitochondria)
Led to discovery of thermogenin in brown adipose tissue
then other uncoupling proteins in muscle.
brown adipose tissue
white adipose tissue
Brown and white adipose tissue in the same region
Brown adipose tissue immunostained for UCP-1
40 µm
Cinti S. Nutrition, Metabolism and Cardiovascular Disease 16: 579-74 2006.
Brown and white adipose tissue in the same region
White adipose tissue
single large lipid droplet
Brown adipose tissue immunostained for UCP-1
multiple small lipid droplets
15 µm
Cinti S. Nutrition, Metabolism and Cardiovascular Disease 16: 579-74 2006.
Transdifferentiation of brown and white adipose tissue
Adipose tissue dissected from a mouse
maintained at 29°C for 10 days.
In response to cold adaptation, areas of white
adipose tissue differentiate into brown adipose
tissue.
In response to a high fat diet, areas of brown
adipose tissue differentiate into white adipose
tissue.
Cinti S. Nutrition, Metabolism and Cardiovascular Disease 16: 579-74 2006.
The ob/ob obese mouse
Parabiosis
Circulating factor from lean animals
suppresses appetite in obese
1994 Zhang et al cloned the ob gene
 expressed in adipose tissue
 peptide has a signal sequence, suggesting it is secreted
Injection of the peptide into obese mice led to weight loss
 called leptin (Greek leptos = lean)
Initial studies showed it acted on the hypothalamic appetite centres
 depressing appetite
 signalling state of adipose tissue reserves
Great excitement that leptin or a leptin agonist would be a cure for obesity,
but obese people secrete higher than normal amounts of leptin
because they have more adipose tissue.
Leptin
The main function of leptin is to signal the state of adipose tissues reserves
and decrease food intake in the long term when they are adequate
Leptin stimulates uncoupling proteins in brown adipose tissue and muscle
so increasing energy expenditure
There is synergy between insulin and leptin in control of food intake
Insulin stimulates leptin synthesis and secretion
Pancreatic islet b-cells have leptin receptors,
leptin increases insulin secretion
Leptin causes insulin resistance / antagonises some actions of insulin
Insulin resistance – the metabolic syndrome
In response to insulin resistance (i.e. hyperglycaemia)
there is increased insulin synthesis and secretion – hyperinsulinism
Signalling through the insulin receptor
insulin


b
b
P
P
ATP
ADP
P
IRS
P
IRS
P
P
P
IRS
P
IRS
P
P
MAPK
PKB
P
protein phosphorylation cascades
rapid (metabolic)
responses
slow (nuclear and mitotic)
responses
Signalling through the insulin receptor
P
P
P
IRS
P
IRS
P
P
MAPK
PKB
Rapid actions via protein kinase B phosphorylation cascade:
 stimulation of glucose transport
 stimulation of glycogen synthesis
 inhibition of lipolysis
 stimulation of fatty acid synthesis
 stimulation of translation / protein synthesis
These responses are impaired in insulin resistance
protein phosphorylation cascades
rapid (metabolic)
responses
slow (nuclear and mitotic)
responses
Signalling through the insulin receptor
P
P
P
IRS
P
IRS
P
P
MAPK
PKB
Slower actions via mitogen-activated protein kinase (MAP kinase)
no role in metabolic actions, involved in nuclear and mitogenic actions
These responses are not affected by insulin resistance
hence exaggerated responses in response to hyperinsulinism
Increased proliferation of vascular smooth muscle
leading to atherosclerosis and hypertension
protein phosphorylation cascades
rapid (metabolic)
responses
slow (nuclear and mitotic)
responses
Insulin resistance – the metabolic syndrome
Possible factors in insulin resistance
 visceral adipose tissue has high lipolytic activity and releases nefa
 nefa inhibit glucose metabolism
 nefa may inhibit the PKB-mediated insulin signalling pathway
 leptin antagonises some actions of insulin
 various cytokines may cause insulin resistance:
 tumour necrosis factor TNF-
 interleukins IL-1 and IL-6
 monocyte chemotactic protein
 resistin
 chemerin
 cortisol may cause insulin resistance
The adipocyte now: a variety of cytokines secreted
cytosol
nucleus
triacylglycerol
complement C3
chemotactic agent for macrophages
White adipose tissue
Adiponectin – low in obesity
Secretion is inversely proportional to adipose tissue mass
Adiponectin
increases insulin-induced tyrosine phosphorylation of insulin receptor
 hence enhances insulin action
 and decreases liver glucose output
 activates 5’-AMP kinases so increases glucose and fatty acid oxidation
 increases expression of genes involved in fatty acid transport and oxidation
 increases expression of uncoupling proteins
 decreases surface expression of vascular adhesion molecules
 inhibits proliferation of vascular smooth muscle cells
 so protective against atherosclerosis and thrombosis
Resistin – increased in obesity
Inhibits adipocyte differentiation
hence possible feedback inhibitor of adipogenesis
Administration to mice increases hepatic glucose production
Hence insulin antagonist
Chemerin
Large adipocytes (from obese subjects) secrete more chemerin per cell
than smaller adipocytes (from lean subjects)
pro-inflammatory actions
chemoattractant for macrophages
Chemerin impairs insulin signalling in muscle by phosphorylation of kinases
reduced glucose uptake in muscle
increased fatty acid uptake and intracellular esterification to TAG
possible lipotoxic effect on muscle
Macrophage infiltration into adipose tissue
lean mouse x 100
obese mouse x 100
obese mouse x 400
stained with toluidine blue
lean mouse x 100
obese mouse x 100
obese mouse x 400
immmunostained with anti-macrophage antibody
Source: Xu H et al, Journal of Clinical Investigation 112:12 1821-30, 2003
Macrophage infiltration into adipose tissue
Macrophages form “crown-like structures” around larger adipocytes that are
really lipid droplets that are the remnants of dead adipocytes.
Hypertrophy of white adipocytes leads to cell death and macrophage
infiltration. There is histological evidence of adipocyte death before
macrophage infiltration.
White adipose tissue is poorly vascularised and blood flow does not
increase in obesity. Large adipocytes are too far from blood vessels to be
adequately oxygenated; hypoxia leads to lactate production, which may be
cytotoxic, leading to macrophage infiltration.
Macrophage infiltration into adipose tissue
The critical size for visceral adipocytes to undergo necrosis and attract
macrophages is smaller than that for sub-cutaneous adipocytes.
Although brown and white adipocytes can undergo trans-differentiation,
• sub-cutaneous adipocytes develop from white adipocyte precursors
• visceral adipocytes arise develop from brown adipocyte precursors.
The evolutionary function of visceral adipose tissue was presumably
thermogenesis; it has differentiated into storage adipose tissue in response
to a high fat diet.
Macrophage infiltration into adipose tissue
Macrophages secrete TNF,
stimulates preadipocytes and endothelial cells
to secrete macrophage attractants
phosphorylates critical serine residues in
insulin receptor and IRS
hence impairs insulin signalling
Source: Wellen KE & Hotamisligil GK, Journal of Clinical Investigation 112:12 1785-8, 2003
Oxidative stress in adipose tissue
Significant positive correlation between:
plasma TBARS and BMI or waist circumference
Significant negative correlation between:
plasma adiponectin and BMI or waist circumference
Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004
Oxidative stress in adipose tissue
Increased oxidative stress
and H2O2 production in adipose tissue
from obese mice
Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004
Oxidative stress in adipose tissue
Decreased activity of
superoxide dismutase and
glutathione peroxidase
in adipose tissue from obese mice
Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004
Oxidative stress in adipose tissue
Elevated expression of NADPH oxidase NADPH + 2 O2 ŽNADP+ + 2 •O2- + 2H+
Reduced expression of antioxidant enzymes
in adipose tissue of obese mice
Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004
Glucocorticoids are formed in adipose tissue
Cushing’s syndrome
abdominal obesity
 insulin resistance / hyperglycaemia
 hypertension
due to excessive production and secretion of corticosteroid hormones
Cortisol acts in the liver to increase gluconeogenesis and glucose release
and in adipose tissue to increase lipolysis and release of nefa
Glucocorticoids are formed in adipose tissue
11-b hydroxysteroid dehydrogenase in adipose tissue
converts inactive cortisone into active cortisol
CH2OH
C
O
CH2OH
O
CH3
OH
C
11-bHSD-1
liver, cns,
adipose tissue
HO
CH3
11-bHSD-2
kidney, colon
cortisone (inactive)
CH3
OH
CH3
O
O
O
cortisol (active)
Plasma levels of cortisol are not elevated in obesity
Cortisol formed in adipose tissue acts in the cells where it is formed
Thiazolidinedione (PPARg agonist)
represses 11bHSD expression in cultured human adipocytes
Glucocorticoids are formed in adipose tissue
Transgenic mice, overexpressing 11bHSD in adipose tissue
 corticosterone unchanged in plasma, increased 15-30% in adipose tissue
 after 15 weeks, body weight 16% higher than controls
 mainly abdominal fat
 hyperglycaemic
 hyperinsulinaemic
 insulin resistant
 serum nefa and TAG elevated
 plasma leptin increased
 leptin resistance – leptin : body fat ratio 2x higher than controls
 resistin expression reduced
 brown fat uncoupling protein expression decreased
Is cortisol production in adipose tissue a factor in the metabolic syndrome?
Is obesity a mild form of Cushing’s syndrome?
Summarised by Wolf G, Nutrition Reviews 60:5 148-51, 2002
Obesity is a disease
There are two problems:
How to lose weight
How to maintain lower body weight