1. Biochemical Aspects of OBESITY
ENDO412

2. What is Obesity ?
Obesity is a: Disorder of Body Weight Regulatory Systems Characterized by Accumulation of Excess body Fat Currently, Obesity is Epidemic as: Abundance of Food & Reduced Activity

3. Why Obesity is Major Problem ?
The risk of Associated Diseases has increased:
- DM
- Hypertension
- Cardiovascular diseases (atherosclerosis etc..)
Childhood Obesity
( 3 fold increase in prevalence over the last decades )

4. Assessment of Obesity Weight in kg BMI = ______________ 2
Aim is to measure amount of body fat
Direct measurement is difficult
Indirect measurement:
Body Mass Index (BMI): correlate with amount of body fat in most individuals
exceptions: athletes : large amounts of lean muscle mass
Weight in kg
BMI = ______________ 2
(height in meters)
less than : Underweight
19.5 – : Healthy
25 – : Overweight
30 or more : Obese

5. Anatomic Differences in Fat Deposition
Anatomic distribution of body fat has a major influence on
associated health risks
Android, Apple-Shaped or Upper Body Obesity
Excess fat in central abdominal area
Waist to Hip > in Men
> in Women
Common in males
Associated with a greater risk of hypertension, insulin
resistance, DM, dyslipidemia & coronary heart diseases
Gynoid, Pear-Shaped or Lower Body Obesity
Excess fat in lower extremities around the hips or gluteal region
Waist to Hip < in Men
< in Women
Relatively benign healthwise
Common in females

6. Biochemical Differences in Regional Fat Depots
Abdominal fat cells: Much larger than lower body fat cells
Higher rate of fat turnover
Hormonally more responsive
More in men: lose weight readily than women
Substances released from abdominal fat (as free fatty acids) are absorbed via portal vein with direct access to the liver
Free fatty acids from abdominal fat taken up by the liver may lead to:
- Insulin resistance
- Increased synthesis of triacylglycerol , released from liver as VLDL --- LDL
resulting in more possibility of hypertirglyceridemia & hypercholesterolemia
Fatty acids from gluteal fat enter the general circulation
- With no preferential action on liver metabolism

7. Obesity & Adipocytes (Number & Size)=
Increase in
Size +
Increase of
Number
of Adipocytes

8. Body Weight Regulation
Each individual has a biologically predetermined
Natural Set Point for body weight
Around which body weight drifts (within 10%)
Reflects a balance between factors that
influence food intake & energy expenditure
The body attempts to:
- Gain weight when the body weight falls below
the set point
- Lose weight when the body weight is higher than
So, body weight is stable as long as the behavioural &
environmental factors that influence energy balance are constant

9. Genetic Contributions to Obesity
Genetic mechanisms play a major role in determining body weight
Obesity is observed clustered in families:
Examples:
If both parents are obese : % chance of the children being obese
If both parents are lean : 9% chance
Identical twins: have very similar BMI (more similar than nonidentical dizygotic twins)
Inheritance of obesity: - Complex Polygenic
Interaction between multiple genes & environment
NOT simple Mendelian genetics (not single gene disorder)

10. Environmental & Behavioural Contributions to Obesity
Environmental & behavioural factors explain the epidemic of obesity over the last decade
(as genetic factor are stable on this short time scale)
Environmental factors:
- Ready availability of palatable energy-dense foods
- Sedentary life-style : TV watching for a long time
Wide dependency on cars
Computer using
Energy-sparing devices at home & at work
Decrease physical activity
Eating behavioural factors:
Snacking
Portion size
Individual`s unique food preferences
Number of people with whom one eats

11. Molecules that Influence Obesity
Afferent signals reach the hypothalamus:
- Neural Signals
- Hormones circulating in blood
- Metabolites
Hypothalamus releases efferent signals (peptides) that influence appetite & energy expenditure

12. Circulating Hormones INSULIN CCK Stomach GHRELIN Adipocytes
LEPTIN RESISTIN ADIPONECTIN
AFFRENTS (to hypothalamus)
EFFRENTS (from hypothalamus)
Nerves & CNS
NOREPINEPHRINE
DOPAMINE
SEROTONIN

13. Hormones of Adipose Tissue
Fat Cells
(Adipocytes)
Store fats
&
Function as Endocrine Cells
Release Many Regulatory Molecules
as Leptin, Adiponectin & Resistin

14. Leptin Leptin is the hormone product of the gene ob
Secreted by fat cells (adipocytes)
Produced proportionally to adipose mass
Acts on the hypothalamus of the brain to regulate the amount of body fat through the control of appetite & energy expenditure
Leptin secretion is : Suppressed by starvation
Enhanced by well-fed state

15. Leptin (cont.)
In Humans (in normal conditions), leptin increases metabolic rate & decreases appetite
In Obese Humans, plasma leptin is normal for their fat mass
indicating the resistance to leptin
Researches Concluded that:
Hypothamic receptors for leptin is produced by db gene
Mutations of db gene produces leptin resistance (experimentally in rodents)
BUT not in most human obesity

16. Ghrelin A peptide secreted primarily in the stomach
The only known Appetite-stimulating hormone in humans
Research:
Injection of ghrelin in the rodents:
Increases food intake
Decreases energy expenditure
Decreases fat catabolism

17. Glucose Intolerance (& DM) Dyslipidemia (Low HDL & Elevated VLDL)
Metabolic Effects of Obesity: Metabolic Syndrome (Insulin Resistance Syndrome or Syndrome X)
Insulin Resistance
Hyperinsulinemia
Glucose Intolerance (& DM)
Dyslipidemia (Low HDL & Elevated VLDL)
Hypertension
WITH SIGNIFICANTLY INCREASED RISK OF DEVELOPING
DM & CARDIOVASCULAR DISORDERS
Men with the syndrome are 3 – 4 times more likely to die from cardiovascular disease

18. Metabolic Effects of Obesity: Insulin Resistance
Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin
Insulin resistance increases with weight gain (overweight & obesity) & diminishes with weight loss (controlling overweight & obesity)
Fat accumulation (OBESITY) causes insulin resistance as:
- Substances produced by fat cells as leptin & resistin may contribute to
development of insulin resistance
- Free fatty acids elevated in obesity is involved in insulin resistance

19. Metabolic effects of obesity: Insulin Resistance & Hyperglycemia (cont
In early stages of insulin resistance
with the absence of defect in b-cell function
obese individuals can compensate
for insulin resistance
by increasing levels of secretion of insulin from b-cells
So, glucose levels in blood remain within normal range
With time (late stages)
b-cells become dysfunctional
(due to fat cells substances , FFA & hyperglycemia)
So, b-cells fail to secrete enough insulin leading to
Increased blood glucose levels (hyperglycemia)

20. Metabolic Effects of Obesity: Dyslipidemia
Insulin resistance in adipose tissues
causes increased activity of hormone-sensitive lipase (deactivated with insulin) resulting
in increased free fatty acids released in blood
In the liver, free fatty acids are converted to cholesterol & triacylglycerol
Excess cholesterol & triacylglycerol are released as VLDL
with
Increased Blood Triacylglycerol & Hyperchlosterolemia
with increased risk of
Coronary Heart Diseases (CHD)

21. Metabolic Effects of Obesity: Dyslipidemia

22. Obesity & Health a Risk Factor for Many Chronic Diseases Obesity is
Type 2 DM
Hypercholesterolemia
High plasma level of triacylglycerol
Hypertension
Coronary Heart Diseases
Some Cancers
Gallstones
Arthritis
Gout

23. Biochemical Principles of Weight Reduction
GOALS of weight management in obese patients:
To induce negative energy balance to reduce body weight
by decreasing caloric intake and/or increase energy expenditure
To maintain a lower body weight over a longer term

24. Weight Reduction: 1- Physical Activity
Benefits:
Increases cardiopulmonary fitness
Reduces risk of cardiovascular diseases (independent on weight loss)
Combination of
Caloric Restriction + Exercise + Behavioural Treatment
is expected to
Reduce 5 – 10 % of weight over a period of 4-6 months
Physical activity is essential for maintaining weight reduction

25. Weight Reduction: 1- Caloric Restriction
1 pound of adipose tissue ( about 0.5 kg) corresponds to about 3500 Kcal
Ineffective for a long term for many obese individuals
More than 90% regain the lost weight after suspension of dieting
Benefits of caloric restriction
Reduction of 10% of weight over a 6-month period often:
- Reduces Blood Pressure
- Reduces Lipid levels
- Enhance Control of Type 2 DM

26. Weight Reduction: 1- Pharmacological Treatment
For BMI 30 or more:
1- Sibutramine:
Appetite suppressant
inhibits serotonin & norepinephrine reuptake
2- Orlistat:
lipase inhibitor that inhibits gastric & pancreatic lipases
It inhibits digestion & hence absorption of about 30% of
diet fat.

27. Weight Reduction: 1- Surgical Treatment
Aims at reducing food consumption
Only indicated for severely obese patients