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The Emerging
Role of Adipose
Tissue
Gareth Denyer
University of Sydney, Australia
Obesity in Australia
Epidemiology of obesity
World perspective
• 50% European adults 35-65 years old are overweight
or obese
• More men overweight, more women obese
• In Western countries, inversely associated with socioeconomic status
UK Foresight study
Female Class V
30
Male Class V
20
Male Class I
Female Class I
10
‘93
‘06
For Aus stats:
www.asso.org.au
navigate to fast facts
The Propaganda
• We are second only to USA
• 52% of Australian women & 67% Australian men
are overweight or obese.
– 2.5 times higher than in 1980.
• Childhood obesity in Australia one of the highest
amongst developed nations.
– 25% overweight or obese.
• Health crisis costing $1.5 billion a year in direct
health costs
• “Fattest people are getting fatter faster”
• “2050 90% adults and 40% children overweight”
From www.asso.org.au
Alternative View
• The recent rise is not as rapid as before
– Greatest rise was 15 years ago
• Speakman Int J Obes (2008) 32 1611-7
– We are all just reaching our ‘set point’
– Previously exercise and low-calorie foods
kept us below the set point
– In the past, only the very rich were fat!
– In developing nations, higher classes fatter
Health Risks of Obesity in Adults
Nurses’ Health Study (women 30 to 55 yr)
Health Professionals Follow-up Study (men 45-60 yr)
Relative Risk
6
5
Women
4
Men
3
2
1
0
21 22 23 24 25 26 27 28 29 30
21 22 23 24 25 26 27 28 29 30
Body Mass Index
Type 2 diabetes
Hypertension
Heart Disease
Cholelithiasis
Morbidity and Mortality
• Increased mortality and morbidity
– >20% of deaths from coronary heart disease
– >70% of cases of Type 2 diabetes
• Chronic Disease
–
–
–
–
–
–
Dyslipidemia
Arthritis
PCOS - polycistic ovarian disease
Sleep apnoea
Hypertension
NAFLD/NASH
• non-alcoholic fatty liver disease, steatohepatitis
Circulating CVD factors
characteristic of obesity
• High cholesterol
– Low HDL, high LDL
• Other dyslipidemia
– Triglyceride concentration
– Small, dense LDLs
– Elevated apoB
• Prothrombotic factors
• High Systolic Blood
Pressure
• Proinflammatory markers
In NSW – 25% of boys and 23% of girls
are overweight or obese (2004)
Health concerns associated with childhood obesity are
similar to adults
Ebbeling. Pawlak, Ludwig: Lancet, 2002
Social and Cultural Impact
• Obviously very difficult to do these studies
– All MUST be adjusted for socioeconomic status
– But several done in Australia
• Employment
– wage ‘penalty’ of up to 12%
• Health Care
– reluctance to seek health care services
– reluctance for doctors to discuss weight with patients
• ‘too difficult’, ‘non-compliant’
• Education
– lower university and tertiary education attendance
• Relationships
– interesting studies with assessment of ‘blind’ interactions vs
photo-prompted
Social Networks
children – peer harassment and rejection
Problem with BMI?
• Classification by Body Mass Index (BMI)
• obese > 30 kg/m2
• overweight > 25 kg/m2
– May not apply to all ages and shapes
• Waist & waist:hip ratio
– Alert –
• Men > 94 cm (37 in), WHR > 0.95
• Women > 80 cm (32 in), WHR > 0.8
– Action –
• Men > 102 cm (40 in)
• Women > 88 cm (35 in)
Apple or Pear? Vague (1947)
Distinct Depots of Fat
Men have more visceral fat
VAT (area, cm2)
250
♂
150
♀
50
10
20
30
% fat
40
50
60
Racial Differences too…
Lancet, 2003
% fat and VISCERAL FAT also higher per BMI in
Caucasian men, African American women and both genders
of Asian’s and Indians
Abdominal Adiposity
Visceral fat is independently linked
with heart disease
Obesity and Coronary Artery
Disease
Lower Body
Normal
Upper Body
100
80
60
40
20
0
BMI Tertiles
Non-obese
Donahue RP, Lancet 1987;1(8537):821-4
Overweight
Obese
Honolulu Heart Study: 7692 men, 12 yr follow-up
Visceral Fat and Glucose
Intolerance
Glucose
mM
Insulin
nM
12
12
9
9
6
6
Upper Body Obesity
Lower Body Obesity
Controls
3
0
3
0
0
1
2
3
Time (h)
Despres et al (1995) Int J Obes 19; S76
0
1
2
Time (h)
3
Visceral/Subcutaneous
• Fat distribution
– gluteo-femoral fat – no problems
– abdominal viscera - diabetes & coronary artery
disease.
• independent of age, overall obesity or the amount of
subcutaneous fat.
• New definition of obesity?
– based on the anatomical location of fat rather than
on its volume,
• Metabolic Obesity
– visceral fat accumulation in either lean or obese
individuals
The Old (!!) view
Adipose as Connective Tissue
• “The individual cells fill
up with fat and the
cytoplasm and the
nucleus are pressed to
the edge of each cell
membrane.”
• “Adipose can be found
under the skin, on the
heart, and around the
kidneys. It serves to
protect, insulate, and
store fat.”
Metabolic Warehouse?
Uptake of Fat after a meal
Synthesis of Fat in
response to insulin
Releasing fatty acids
into the bloodstream
during starvation and
exercise
Very dynamic – huge fluxes after meals & during starvation
Adipocyte size is very flexible
New view
Largest Endocrine Organ!!
Leptin
Hypothalamus
LIPOSTAT
ADIPOSTAT
Leptin
Receptors
Energy Intake
Adipocytes
Fat Storage
Metabolic Rate
Early Enthusiasm for Leptin
After
People without leptin are hyperphagic
..and they respond to leptin injections
100
Body Weight (kg)
Before
Leptin
50
0
0
3
6
9
Age (years)
So could leptin injections be the
‘cure’ for obesity?
Leptin and Obesity
– More and bigger WAT cells
– Leptin higher in women
– Sex hormone interactions
• Extra leptin is ineffective
– leptin-resistant… why?
– Small changes in leptin
may not be meaningful
• Rather than a excess of
leptin telling us to stop
eating, a lack of leptin may
tells us to start eating
100
Serum Leptin (ng/ml)
• Obese people higher blood
[leptin]
50
0
0
20
40
Body fat (%)
60
Adipokines – molecules secreted by
adipose tissue
• Leptin receptors are like cytokine
receptors
– Adipocytokines… Adipokines
• Many more discovered!
– Affecting more than just appetite and
metabolic rate
– Over 50 known protein and signal molecules
Lots of Adipokines
BLOOD PRESSURE
angiotensin
APPETITE
leptin
LIPID METABOLISM
Cholesterol ester
transfer protein
IMMUNITY
ANGIOGENESIS
VEGF
INFLAMMATORY
CYTOKINES
TNF-α
Interleukin-6
C-reactive protein
complement
proteins (adipsin)
HEMOSTASIS
PAI-I (plasminogen
activator inhibitor-I)
INSULIN SENSITIVITY
adiponectin
resistin
visfatin
CELL ADHESION
intercellular adhesion
molecule -1
WAT is not all Adipocytes
• Other cells comprise
adipose tissue
– stromal-vascular cells
– pre-adipocytes (stem cells)
– macrophages
• Macrophages also secrete
a range of cytokines
– So the adipokines coming
from WAT may not always
be adipocyte-derived
– Resistin best example
• rodents in adipocytes,
macrophages in humans
Obesity as Inflammation
• Big fat cells and big fat pads produce large
amounts of adipokines
– except adiponectin
• adiponectin produced by small fat cells
• As fat stores get bigger
– increased mix of inflammatory cytokines
– increased blood coagulation potential
– increased blood pressure
• WAT is potentially the BIGGEST endocrine
organ!
– Affecting many tissues and homeostatic processes
Adipokines of Interest
• Inflammatory cytokines
– the link between adiposity and heart disease?
• Interleukin-6 – high in obese. More from visceral.
• Plasminogen activator inhibitor 1 (PAI-1) – high in obese
• C-reactive protein - liver and also in adipose tissue
• Adipokines that affect insulin sensitivity
– the link between adiposity and Type II diabetes?
• TNF-α – insulin resistance in muscle (IRS interference)
• visfatin – produced by visceral fat
• adiponectin – produced by small adipocytes
• Inflammatory and resistance markers especially
raised in VISCERAL ‘obesity’
– but cause or effect?
• 10% of cells in WAT
–
–
–
–
Much higher in obese fat pads
More “activated” in obese
Even fuse to form giant
multinuclear cells
• Source?
% macrophages
Macrophages
60
40
20
0
0
5,000
10,000
Average adipocyte area (µm2)
– Stem cells in WAT can become macrophages
– But likely to be trapped by increased local expression
of ICAM-1
• Macrophages really similar to adipocytes
– Both can carry fat (remember foam cells)
• May be there to mop up fat from large, burst cells
Dying Fat Cells
Macrophages (green)
Cluster around fat cell
Macrophage Infiltration
Not all adipokines are proteins…
• Cell 134, 933–944, September 19, 2008
Systemic lipid proﬁling also led to
identiﬁcation of C16:1n7-palmitoleate as
an adipose tissue-derived lipid
hormone that strongly stimulates
muscle insulin action and suppresses
hepatosteatosis.
Lifestyle Management
diet and physical activity
• How much weight loss is appropriate to aim for?
• ‘ideal’ weight probably unachievable
– MAINTAIN (don’t put on more)
• this may be the best option
– LOSE 5-10%
• even this results in 20% less mortality, 10 mmHg
drop in blood pressure, 15% lowering of
lipids/cholesterol, etc
Dietary Therapy for Obesity: An Emperor With No
Clothes Hypertension. June 2008;51:1426-1434
“Over 5 decades, it has
been demonstrated
repeatedly that dietary
therapy fails…”
“In an era when we pride ourselves
on practicing evidence-based
medicine, why then does dietary
and behavioral therapy still reign?”
Why bother with lifestyle?
• General pessimism regarding ability to maintain
reduced weight with lifestyle changes alone
• US NHANES study
– 1310 people who lost 10% BW
– 60% maintained weight loss at 1 yr
• Factors predicting weight maintenance
– Close monitoring of food intake
– Regular exercise
– Regular monitoring of weight
Voelker R 2007, JAMA V298, pp 272-3
Bariatric Surgery
• Manipulation of the Digestive system
– Malabsorbtive
• shorten the digestive tract
• by-pass the small intestine or parts of it
– Restrictive
• reduce the size of the stomach
http://www.bariatricsurgeons.com/options.htm
Banding
O’Brien & Dixon (2006) in
Clinical Obesity, Kopelman et al
Laproscopic adjustable
gastric band (LAGB)
Minimally invasive
Adjustable (even reversible)
Small Bowel By-Pass
O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al
Stapling & Biliopancreatic By-Pass
Still 250 ml stomach
O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al
Banding
• Convenient
– 35 min operation
– Inexpensive, Not permanent
• Safe
– 0.05% deaths
– Late complications common (15%)
• Slippage, infection, stomach erosion, leakage
• Relatively slow weight loss
– But >50% excess weight (EW) loss over 2 years
• Some lose 120% EW
– But easy to ‘cheat’
Roux en Y (Gastric Bypass)
• Small stomach, less digestive juice
– Restriction and malabsorbtion
• 80% excessive weight loss
• Stop diabetic medication
– 85% cure from Type II diabetes
– IN TWO DAYS!!!!
– “Metabolic Surgeons”
• All other obesity related problems affected
– Angina, hypertension, sleep apnoeas, arthiritis
• Skin excess a big disadvantage
– Also hair thinning, gall stones
• 90 min operation, 0.5% deaths
– Cutting and joining… Leak 2%
– Cheating still possible if force stomach to stretch!
Diabetes Reversal
• Very rapid
– Within a few days
– Even before any significant weight loss
– Same applies to sleep apnoea
• Mechanism?
– Food-gut interactions affecting incretin
secretion?
– Intestinal gluconeogenesis appears to be key
• Cell Metab 2008 Sep 8(3):201-11
– But still not clear how the communication works
Sustained Weight Loss
N Eng J Med 357;8
(2007)
Short vs Long term costs?
N Eng J Med 357;8
(2007)
Costs of Surgery soon Recouped
• Diabetes Care 2009;32:567-574 and 580-584.
• Randomised controlled study in Melbourne
• Looking at Type 2 diabetes in obese patients
– Surgery vs drug/diet interventions
• Surgically induced weight loss is cost-effective
relative to conventional therapy
– in the short term (2 years)
– projected over a patient's lifetime
Bariatric Surgery in Australia
• 1996 frequency was 1.2 per 100,000
– In 2006 it was 36 per 100,000
• In 2008 12,000 banding operations performed
• Many see as the ONLY option
– Ensures compliance
– Reversal of diabetes
• Can we persevere with lifestyle therapy?
• Surely this can’t be the answer….
– And would we recommend it for children?!