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Biochemical Aspects of
OBESITY
ENDO412
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
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 )
Assessment of Obesity
•
•
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
BMI =
Weight in kg
______________
2
(height in meters)
less than 19.5
19.5 – 25
25 – 29.9
30 or more
: Underweight
: Healthy
: Overweight
: Obese
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 > 1 in Men
> 0.8 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 < 1 in Men
< 0.8 in Women
Relatively benign healthwise
Common in females
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
Obesity & Adipocytes (Number & Size)
Obesity
=
Increase in
Size
+
Increase of
Number
of Adipocytes
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
the set point
So, body weight is stable as long as the behavioural &
environmental factors that influence energy balance are constant
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 : 70-80% 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)
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
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
Stomach
GHRELIN
Adipocytes
LEPTIN
RESISTIN
ADIPONECTIN
Nerves & CNS
NOREPINEPHRINE
DOPAMINE
SEROTONIN
EFFRENTS (from hypothalamus)
AFFRENTS (to hypothalamus)
Circulating
Hormones
INSULIN
CCK
Hormones of Adipose Tissue
Fat Cells
(Adipocytes)
Store fats
&
Function as Endocrine Cells
Release Many Regulatory Molecules
as Leptin, Adiponectin & Resistin
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
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
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
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
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
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)
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)
Metabolic Effects of Obesity:
Dyslipidemia
Obesity & Health
Obesity is
a Risk Factor for Many Chronic Diseases
Type 2 DM
Hypercholesterolemia
High plasma level of triacylglycerol
Hypertension
Coronary Heart Diseases
Some Cancers
Gallstones
Arthritis
Gout
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
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
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
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.
Weight Reduction:
1- Surgical Treatment
• Aims at reducing food consumption
• Only indicated for severely obese patients