OBESITY

The Simplified Model

Obesity Trends Among U.S. Adults
between 1985 and 2002
Definitions:
Obesity: having a very high amount of body fat in relation to
lean body mass, or Body Mass Index (BMI) of 30 or higher
Body Mass Index (BMI): a measure of an adults weight in
relation to his or her height, specifically the adults weight in
kilograms divided by the square of his or her height in meters
 5

Classification and Diagnosis

Classification BMI (kg/m2) Risk of Co-morbidities
Underweight <18.5 increased risk in other areas

Desirable 18.5-24.9 Average

Overweight 25.0-29.9 Mildly Increased
Obese >30.0
Class I Obesity 30.0-34.9 Moderate
Class II Obesity 35.0-39.9 Severe

Class III Obesity >40.0 Very severe

 6

Classification for Children (<2 Years)

BMI Status
Normal weight for height 10th-90th percentile
At risk for overweight 85th-95th percentile
Overweight >95 percentile

(Centre for Disease Control and Prevention, 2005)

 7

Assessing Obesity
Waist circumference at level of iliac crest
Above 40 inches for men and 35 inches for
women are indicative of health risk.
Waist-to-hip ratio: Circumference of the waist at the
level of L3 divided by the circumference of the hip at
the largest area of the gluteal region. (Helps identify
central or android obesity.)
For men waist-to-hip ratio > 1
For women waist-to-hip ratio > 0.85
 17

Energy Balance
State in which energy intake, in the form of food and /or alcohol, matches
the energy expended, primarily through basal metabolism and physical
activity
Positive energy balance
Energy intake > energy expended
Results in weight gain
Negative energy balance
Energy intake < energy
Results in weight loss
 16

Energy Production
 19

Regulation of Energy Intake and

Body Weight
Factors that regulate energy intake and body weights
are:
Dietary thermogenesis and the Thermic Effect of Foods (TEF)
Resting/Basal Metabolic Rate (RMR)/(BMR)
Energy expended in voluntary activity
Regulatory neurotransmitters and hormones
 29

Brain Neurotransmitters
Norepinephrine and Dopamine
Released by symphathetic nervous system (SNS)
Fasting & starvation SNS activity, epinephrine that govern
feeding behaviour
Dopaminnergic pathway in the brain play a role in
reinforcement properties of foods.
Serotonin
In serotonin leads to carbohydrate appetite.
Corticotrophin-releasing Factor (CRF)
CRF is a potent anorexic agent and weakens the feeding
response produced by norepinephrine and neuropeptide Y.
CRF is released during exercise.
 30

Gut Hormones
Incretins is a G-I peptide
insulin release after eating , even before blood glucose level
is elevated. Serotonin is a G-I peptide
Cholecystokinin (CCK)
At brain level inhibits food intake. Stimulates pancreatic
enzymes
Bombesin
Food intake and enhances the release of CCK.
Enterostatin
Part of pancreatic lipase; satiety following fat consumption
 Gut Hormones 31

Adiponectin - Adipocytokine secreted by adipose tissue

Level of this hormone is inversely related to BMI. Plays role in
metabolic disorders.
Glucagon causes hypoglycemia
Glucagon-like-peptide-1 (GLP-1)
Released in presence of glucose rich food, delays gastric emptying
time and promote satiety.
Leptin is an adipocytokine and regulates appetite.
In obesity it loses the ability to inhibit energy intake.
Resistin - An adipocytokine that antagonizes insulin action
Ghrelin Produced in stomach and stimulate hunger.
Peotide YY-3-36 (PYY -3-36 ) is secreted in small bowel in response to foods.
In obesity it loses the ability to inhibit energy intake.
 32

Other Hormones
Thyroid hormone Modulates the tissue responsiveness to the
catecholamines secreted by SNS. thyroid hormone lowers the SNS
activity and adaptive thermogenesis.
Vispatin - An adipocytokine protein that has an insulin-like-effect.
Plasma level with adiposity and insulin resistance.
Adrenomedullin - A new peptide secreted by adipocytesas a result of
inflammatory process
 33

Satiety Regulator
The hypothalamus
When feeding cells are stimulated, they signal us to eat
When satiety cells are stimulated, they signal us to stop eating
Sympathetic nervous system
When activity increases, it signals us to eat
When activity decreases, it signals us to stop eating
 34

Influences of Satiety
Diseases Associated with Obesity

Diabetes: 80% related to obesity

Hypertension: prevalence is >40% in obesity
Heart disease: 70% related to obesity
Cancer: Obesity accounts for 15-20% of cancer-related deaths
Death: Obese individuals have a 50-100% increased risk of
death from all causes compared to lean individuals (most of
this risk is due to cardiovascular disease)
 The Metabolic Syndrome

Central obesity
Glucose intolerance
Hypertension
Insulin resistance

High TG
Low HDL-C
Small, dense LDL particles

1998 PPS
 Traditional CHD Risk Factors

Elevated Plasma Cholesterol

Reduced Plasma HDL Levels
Diabetes
Hypertension
Smoking
Age New Markers
Inflammatory
Adipokines

Lipid Lowering only results in a relative risk

reduction of 30%
New Inflammatory Markers to assess Risk

CRP
IL-6
TNFa
Serum Amyloid A
Non-esterified fatty acids

Adipose tissue is an important source of

inflammatory cytokine production
White Adipose Tissue (WAT)
Many different adipose tissue beds throughout the whole
organism
Many distinct cell types: adipocytes, pre-adipocytes, fibroblasts,
macrophages, vascular cells
Heterogeneous metabolic capabilities, depending on visceral or
subcutaneous location of fat depot
Secrete adipokines with systemic effects
WAT is central to energy storage in the body and the
mobilization of this energy store is highly regulated.
 Basic Adipose Tissue Expansion

Preadipocyte Mature adipocyte

http://www.hsph.harvard.edu/GSHLAB/adipos.html
Adipocyte Growth:
Hypertrophy vs. Hyperplasia
Hypertrophy (increase in size) Lipogenesis
Result of excess triglyceride accumulation in existing adipocytes

Hyperplasia (increase in number)

adipogenesis results from the recruitment of new adipocytes from
precursor cells in adipose tissue and involves proliferation and
differentiation

Hausman et al. Obesity Reviews (2001) 2, 239-254

 Hormones, Adipokines, enzymes, molecules and other factors reportedly
associated with Adipose Tissue
Cytochrome p450-dependent aromatase (P450arom)
E2F proteins
Ecto-nucleotide pyrophosphatase/phosphodiesterase 1
Nitric oxide synthase
Eicosanoids
Nuclear factors
Endothelin
Omentin
Entactin/nidogen
Osteonectin (secreted protein, acidic and rich in cystein/SPARC)
Eotaxin
Pentraxin-3
Epidermal growth factor
p85aphosphatidylinositol 3-kinase
Estrogen
Perilipins
Fasting-induced adipose factor
Phosphoenolpyruvate carboxykinase
Fatty acid translocase
Phospholipid transfer protein
Fatty acid transport protein
Pigment epithelium-derived factor
Fibroblast growth factor
Plasminogen activator inhibitor
Free Fatty Acids
Pre-adipocyte factor-1
Galectin-12
Prolactin
Gelsolin
Protein kinases
Glucose transporter 4
Protease inhibitors (e.g., cystatin C and Colligin-1)
Glutamine
Prostaglandin E, I2 and F2 prostacyclins (PGI2/PGF2)
Glycerol
Regulated on activation, normal T-cell expressed and secreted (RANTES)
Haptoglobin
Renin
Hippocampal cholinergic neurostimulating peptide
Resistin (FIZZ3 or serine/cystein-rich adipocyte-specific secretory factor [ADSF])
Hormone-sensitive lipase
Resistin-like molecules
Insulin-like growth factor
Retinol
Insulin-like growth factor binding protein
Retinol-binding protein
Interleukin-1, -6, -8, and -10
Sergin protease inhibitors
Interleukin-1 receptor antagonist
Serum amyloid A
Lactate
Stearoyl-CoA desaturase
Leptin
Stromal cell-derived factors (e.g., stromal cell-derived factor 1 precursor or pre-B
Lipin growth stimulating factor)
Lipocalins Tissue factor
Lipoprotein lipase Tonin
Lysophospholipid Transforming growth factor-
Macrophage migration inhibitory factor Tumor necrosis factor-a
Metalloproteases UDP-glucuronosyltransferase A242B15
Metallothionein Uncoupling proteins
Monobutyrin Vascular endothelial growth
Monocyte chemoattractant protein-1 Visceral adipose tissue-derived serpin
Necdin Visfatin (pre- cell colony-enhancing factor [PBEF])
Nerve growth factor
Neuronatin

Bays H & Ballantyne C; Future Lipidol 2006; 1(4): 389-420

Free Fatty Acids (FFA)
Adipose tissue serves as a buffer for FFA levels following feeding
(similar to the way liver buffers blood glucose levels)
FFA are released from WAT when systemic energy needs are not
being met
FFA levels are a predictor of future development of type 2
diabetes
Effects of elevated plasma FFA levels

Insulin resistance in muscle

Inhibition of normal function of insulin to suppress hepatic
glucose production
Impair insulin-stimulated glucose uptake
FFA are substrate for hepatic triglyceride synthesis leading to
increased plasma VLDL and triglyceride levels
Impair endothelial function
Control of Release of FFA From White Adipose Tissue

Lipid storage WAT

Diet

Starvation

Insulin Resistance Lipolysis Insulin

Free Fatty Acid

Liver
Ketone
Phospholipids
bodies
Triglycerides

Hypertriglyceridemia Atherosclerosis
Secretory Products of Adipose Tissue

Bone
IGF-1 TNF-
Morphogenic Fatty Acids
IGFBP Interleukins
Resistin Protein Lactate
TGF
FGF Adenosine
EGF Prostaglandins
Glutamine
Adiponectin Adipose
Tissue Unknown Factors

Estrogen

Ang II

PAI-1
Angiotensinogen Leptin

Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S
Adipokines
Vascular Disease Related
Angiotensinogen
PAI-1
Insulin Resistance Related
ASP (Acylation-stimulating protein)
TNFa
IL-6
Resistin
Leptin
Adiponectin
Angiotensinogen (AGE)
Links obesity with hypertension
Positive correlation of blood pressure with AGE levels
Primarily produced in liver, but also by WAT
Deficiency partially protects against diet-induced obesity
Plasminogen Activator Inhibitor 1 (PAI-1)

Impairment of fibrinolytic system contributes to

cardiovascular complications of obesity
WAT is main tissue source of PAI-1
Produced by pre-adipocytes, primarily in visceral
WAT
Acts to inhibit fibrinolysis (is pro-thrombotic)
Also influences cell migration and angiogenesis
Could impair pre-adipocyte migration leading to
WAT growth
TNFa

Proinflammatory cytokine
Produced by adipocytes and macrophages in WAT
Over-expressed in obesity
Link between TNFa and insulin resistance
Alters insulin signaling and MAPK pathways in vitro and in vivo
IL-6

10-30% of circulating IL-6 is from WAT

Highly correlated with body mass and inversely related to insulin
sensitivity
Alters insulin signaling in the liver
IL-6 KO mice develop mature-onset obesity and glucose
intolerance
Resistin

Discovered in 2001
Expressed in adipocytes in mice and in macrophages
in humans
Increased in obesity
Recombinant resistin
Promotes insulin resistance in mice
Decreased insulin stimulated glucose uptake in WAT
Leptin

Secreted by adipocytes
Regulates food intake satiety factor
Leptin receptor is expressed in hypothalamus