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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

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The emerging role of adipose tissue

The Emerging Role of Adipose Tissue

Gareth Denyer

University of Sydney, Australia

Epidemiology of obesity world perspective
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 socio-economic status

UK Foresight study

Female Class V


For Aus stats:

navigate to fast facts

Male Class V


Male Class I

Female Class I




The propaganda
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”


Alternative view
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

Body Mass Index

Morbidity and mortality
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


      • non-alcoholic fatty liver disease, steatohepatitis

Circulating cvd factors characteristic of obesity
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

Health concerns associated with childhood obesity are similar to adults

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
Social and Cultural Impact obese

  • 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
Social Networks obese

children – peer harassment and rejection

Problem with bmi
Problem with BMI? obese

  • 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
    Apple or Pear? obese Vague (1947)

    Men have more visceral fat
    Men have more visceral fat obese



    VAT (area, cm2)








    % fat

    Racial Differences too… obese

    Lancet, 2003

    % fat and VISCERAL FAT also higher per BMI in

    Caucasian men, African American women and both genders of Asian’s and Indians

    Obesity and coronary artery disease

    Lower Body obese


    Obesity and Coronary Artery Disease

    Upper Body




    12 y CAD Risk/1000




    BMI Tertiles




    Honolulu Heart Study: 7692 men, 12 yr follow-up

    Donahue RP, Lancet 1987;1(8537):821-4

    Visceral fat and glucose intolerance
    Visceral Fat and Glucose Intolerance obese







    Upper Body Obesity





    Lower Body Obesity














    Time (h)

    Time (h)

    Despres et al (1995) Int J Obes 19; S76

    Visceral subcutaneous
    Visceral/Subcutaneous obese

    • 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 Old (!!) view obese 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
    Metabolic Warehouse? obese

    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

    Obesity metabolic inflexibility
    Obesity - Metabolic Inflexibility obese

    Activity of Visceral fat in fasted subjects

    Meal (100 g carbohydrate)



    FA release (nmol/ml/min)


    • Obese vs. normal

    • Less suppression after meal

    • Continual release even when fed

    • Less release during fasting




    Time after meal (min)

    Nefa control
    NEFA Control obese

    • Fatty acid buffering is reduced in obesity

      • Overspills into the other tissues

      • inappropriate accumulation of fat in muscles and liver

      • leading to insulin resistance and steatosis

    • Visceral fat especially good at releasing NEFA

      • Into portal circulation so to liver first

      • especial effect on glucose and VLDL output

    New view largest endocrine organ
    New view obese Largest Endocrine Organ!!





    Leptin Receptors

    Energy Intake

    Metabolic Rate


    Fat Storage

    Early enthusiasm for leptin
    Early Enthusiasm for Leptin obese



    • People without leptin are hyperphagic

      • ..and they respond to leptin injections



    Body Weight (kg)







    Age (years)

    So could leptin injections be the ‘cure’ for obesity?

    Leptin and obesity
    Leptin and Obesity obese


    • Obese people higher blood [leptin]

      • 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

    Serum Leptin (ng/ml)







    Body fat (%)

    Adipokines molecules secreted by adipose tissue
    Adipokines – molecules secreted by adipose tissue obese

    • 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




    Cholesterol ester transfer protein





    complement proteins (adipsin)









    C-reactive protein


    PAI-I (plasminogen activator inhibitor-I)


    intercellular adhesion molecule -1

    Lots of Adipokines

    Wat is not all adipocytes
    WAT is not all Adipocytes obese

    • 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
    Obesity as Inflammation obese

    • 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
    Adipokines of Interest obese

    • 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?

    Macrophages obese


    • 10% of cells in WAT

      • Much higher in obese fat pads

      • More “activated” in obese

      • Even fuse to form giant

      • multinuclear cells

    • Source?

      • 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


    % macrophages






    Average adipocyte area (µm2)

    Dying fat cells
    Dying Fat Cells obese

    Macrophages (green)

    Cluster around fat cell

    Not all adipokines are proteins
    Not all adipokines are proteins… obese

    • 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.

    Wat affects other tissues
    WAT affects other tissues obese

    • WAT is the most insulin sensitive tissue

      • Although total responsiveness is not great

      • Metabolically relatively inactive

      • Glucose disposal slow in comparison to muscle

      • Low contribution to glucose disposal on a whole body basis

    • BUT fatty acid and adipokine release affects insulin action in other tissues

    • Even in normal weight people, WAT can be 25% of body weight

      • Can range from 3% (male elite athlete) to 70% (very obese)

    Examples obese

    • Anti-diabetic thiazolidinedione drugs

      • increase insulin sensitivity in WAT

      • Change the adipokine profile

      • Increase production of new fat cells which produce adiponectin

    • Knockout of GLUT-4 in WAT

      • Widespread insulin resistance in muscle and liver

      • Even though WAT size unaffected

    Effects of wat loss
    Effects of WAT loss obese

    • Lipodystrophy

      • Lack of adipose tissue

    • Accompanied by

      • Insulin resistance

      • Type II diabetes

      • Dyslipidemia (high triglycerides, low HDL)

      • Hepatic and muscle fat accumulation

        • Hepatic steatosis and cirrhosis

      • Some sexual abnormalities

        • Lack of ovulation, infertility

        • Excess of male hormones  hirsuitism

    Lipodystrophies obese

    • Inherited

      • Defects in genes that control adipocyte development

    • Acquired

      • HIV patients receiving protease inhibitors

        • >100,000 protease-induced lipodystrophies in USA

        • Impairment of adipocyte differentiation

        • But only in some depots

          • Loss of subcutaneous fat in face, arms, legs

          • Others depots compensate

          • Exaggerated shapes (eg, thin, drawn face, very wide hips)

      • Sleep apnoea after HIV treatment

        • International Journal of STD & AIDS 2006; 17: 614–620

    Transplantation obese

    • Removal of fat from one site

      • Compensatory increase in size of other depots

      • Dynamic

        • In hibernating animals or animals in which fat is laid down ‘seasonally’ the “correct” level of fat is re-made

    • Grafting experiments

      • Pads grafted are not ‘noticed’ by the animal

        • No compensatory changes – not ‘lipostatically’ active

      • UNLESS…

        • Donor pads are grafted touching another pad…

        • Implies paracrine interactions between the pads

    Whole body effects
    Whole Body Effects obese

    • Transplant WAT into lipoatrophic animals

      • Restores glucose tolerance

      • But the transplanted fat has to be good “quality”

        • Small, active adipocytes good

        • Triglyceride laden, old adipocytes do not help

    • Transplantation of young, insulin sensitive adipocytes into insulin resistant animals

      • Restores glucose tolerance

    • Subcutaneous/visceral transplants

      • Show depots are intrinsically distinct

      • More subcutaneous improves insulin sensitivity

    Does fat cell number change
    Does fat cell number change? obese

    • Nature 2008 June 5; 453(7196) p783-7

    The number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss.

    The number of adipocytes is set during childhood and adolescence.

    Approximately 10% of fat cells are renewed annually at all adult ages and levels of BMI.

    Spalding, 2008 obese Nature



    Hyperplasia and hypertrophy
    Hyperplasia and Hypertrophy obese

    even with 6 months calorie restriction, no apoptosis

    weight loss

    cell number constant




    weight gain


    larger potential for fat deposition?

    Stages of weight gain
    Stages of Weight Gain obese

    • Involves both hyperplasia and hypertrophy

      • Hypertrophy occurs first

      • Then pre-adipocytes proliferate

      • Then differentiation into new adipocytes

      • NB. Large adipocytes secrete factors which initiate differentiation

    • Specific depots have different types of growth

      • Some evidence that visceral fat cells may get larger

      • … whereas subcutaneous may proliferate more

    Fat cell size
    Fat Cell Size obese

    • Large cells

      • Increased secretion of inflammatory adipokines

    • Young, small cells

      • Increased secretion of adiponectin

    • Small cells that used to be big?

    • Hypoxic fat cells

      • Poor blood supply to extremities in fat pads

      • Inflammatory adipokine profile

      • E.g., CCL5

    Current research
    Current Research obese

    • Study fat cells as they change their size

    • Techniques

      • Microarrays to study gene expression

      • Proteomics to study protein changes

    • Models

      • Cell culture

        • Problem with lifespan

      • Isolated adipocytes… from different depots

        • Fractionate into large/small

      • Whole animal - diets

        • Difficult to distinguish effects of diet from effects of changing cell size

        • Cell size  macrophage accumulation  adipokines

    Serendipity… obese

    Our colleagues in Pharmacology were looking at the ability of adipose tissue to take up and release THC


    Vehicle control

    What s happening
    What’s Happening? obese

    • No increased caloric intake

    • Larger, fewer cells

    • Repackaging?

      • Fat from dying cells redistributed?

      • Would expect to see re-esterification of fat

      • This requires glycerol 3-phosphate

    PEPCK vital in glyceroneogenesis obese

    Over-expression causes more fat accumulation

    Therapy in australia
    Therapy in Australia obese

    • Diet and Lifestyle

    • Drugs

    • Bariatric Surgery

    Lifestyle management diet and physical activity
    Lifestyle Management obese 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
    Why bother with lifestyle? obese

    • 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
    Bariatric Surgery obese

    • 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

    Banding obese

    O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al

    Laproscopic adjustable gastric band (LAGB)

    Minimally invasive

    Adjustable (even reversible)

    Small bowel by pass
    Small Bowel By-Pass obese

    O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al

    Stapling biliopancreatic by pass
    Stapling & Biliopancreatic By-Pass obese

    Still 250 ml stomach

    O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al

    Banding obese

    • 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
    Roux en Y (Gastric Bypass) obese

    • 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
    Diabetes Reversal obese

    • 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
    Sustained Weight Loss obese

    N Eng J Med 357;8 (2007)

    Short vs Long term costs? obese

    N Eng J Med 357;8 (2007)

    Costs of surgery soon recouped
    Costs of Surgery soon Recouped obese

    • 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
    Bariatric Surgery in Australia obese

    • 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?!