Biochemical Aspects of Biochemical Aspects of OBESITYOBESITY

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What is What is ObesityObesity ??

Obesity is a:Obesity is a:Disorder of Body Weight Regulatory Systems Disorder of Body Weight Regulatory Systems

Characterized byCharacterized by Accumulation of Excess body FatAccumulation of Excess body Fat

Currently, Obesity is Epidemic asCurrently, Obesity is Epidemic as:: Abundance of FoodAbundance of Food

&& Reduced Activity Reduced Activity

WhyWhy ObesityObesity is is Major Problem Major Problem ??

• The risk of The risk of AssociatedAssociated DiseasesDiseases has increasedhas increased:: - - DMDM - Hypertension- Hypertension - Cardiovascular diseases (atherosclerosis etc..) - Cardiovascular diseases (atherosclerosis etc..)

• Childhood ObesityChildhood Obesity ( 3 fold increase in prevalence over the last decades )

Assessment of ObesityAssessment 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

Weight in kgWeight in kg BMI = ______________BMI = ______________ 22

(height in meters)(height in meters)

less than 19.5 : Underweightless than 19.5 : Underweight 19.5 – 25 : Healthy19.5 – 25 : Healthy 25 – 29.9 : Overweight25 – 29.9 : Overweight 30 or more : Obese30 or more : Obese

Anatomic Differences in Fat DepositionAnatomic Differences in Fat Deposition

Anatomic distribution of body fat has a major influence on Anatomic distribution of body fat has a major influence on

associated health risksassociated health risks

• Android, Apple-Shaped or Upper Body Obesity 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 malesmales Associated with a greater risk greater risk of hypertension, insulin resistance, DM, dyslipidemia & coronary heart diseases

• Gynoid, Pear-Shaped or Lower Body Obesity 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 WomenRelativelyRelatively benign healthwise benign healthwise Common in femalesfemales

Biochemical Differences in Regional Fat DepotsBiochemical Differences in Regional Fat Depots

• Abdominal fat cellsAbdominal fat cells: Much larger than lower body fat cellsMuch larger than lower body fat cells Higher rate of fat turnoverHigher rate of fat turnover Hormonally more responsiveHormonally more responsive More in men: lose weight readily than womenMore in men: lose weight readily than women

• Substances released from abdominal fat (as free fatty acids) are absorbed via Substances released from abdominal fat (as free fatty acids) are absorbed via portal vein with direct access to the liver portal vein with direct access to the liver

Free fatty acids from abdominal fat taken up by the liver may lead to:Free fatty acids from abdominal fat taken up by the liver may lead to: - - Insulin resistanceInsulin resistance - Increased synthesis of triacylglycerol , released from liver as VLDL --- LDL- Increased synthesis of triacylglycerol , released from liver as VLDL --- LDL resulting in more possibility of hypertirglyceridemia & hypercholesterolemiaresulting in more possibility of hypertirglyceridemia & hypercholesterolemia

• Fatty acids from gluteal fat enter the general circulationFatty acids from gluteal fat enter the general circulation - With - With nono preferential action on liver metabolism preferential action on liver metabolism

Obesity & Adipocytes (Number & Size)Obesity & Adipocytes (Number & Size)

Obesity Obesity

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Increase in Increase in

SizeSize

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NumberNumber

of Adipocytesof Adipocytes

Body Weight RegulationBody Weight Regulation

Each individual has a biologically predetermined Each individual has a biologically predetermined Natural Set PointNatural Set Point for body weightfor body weight

• Around which body weight drifts (within 10%) • Reflects a balancebalance between factors that • influence food intake & energy expenditure• The body attempts to: - Gain weight Gain weight when the body weight falls below the set point - LoseLose weight weight when the body weight is higher than the set point

So, body weight is So, body weight is stablestable as long as the behavioural & as long as the behavioural &environmental factors that influence energy balance are consenvironmental factors that influence energy balance are constant tant

Genetic Contributions to ObesityGenetic Contributions to Obesity

• Genetic mechanisms play a Genetic mechanisms play a major role major role in determining body weightin determining body weight• Obesity is observed Obesity is observed clustered in families:clustered in families: ExamplesExamples: If both parents are obese : 70-80% chance of the children being obese If both parents are obese : 70-80% chance of the children being obese If both parents are lean : 9% chanceIf both parents are lean : 9% chance Identical twins: have very similar BMI (more similar than nonidentical dizygotic twins)Identical twins: have very similar BMI (more similar than nonidentical dizygotic twins)

• Inheritance of obesityInheritance of obesity: - : - Complex Polygenic Complex Polygenic Interaction between Interaction between multiple genes multiple genes & & environmentenvironment NOTNOT simple Mendelian genetics simple Mendelian genetics (not single gene disorder) (not single gene disorder)

Environmental & Behavioural Environmental & Behavioural Contributions to ObesityContributions to Obesity

• Environmental & behavioural factors explain the epidemic of obesity Environmental & behavioural factors explain the epidemic of obesity over the last decade over the last decade

(as genetic factor are stable on this short time scale) (as genetic factor are stable on this short time scale)

• Environmental factorsEnvironmental factors: - - Ready availability of palatable energy-dense foodsReady availability of palatable energy-dense foods - - Sedentary life-style Sedentary life-style : : TV watching for a long timeTV watching for a long time Wide dependency on cars Wide dependency on cars Computer using Computer using Energy-sparing devices at home & at workEnergy-sparing devices at home & at work Decrease physical activityDecrease physical activity

• Eating behavioural factorsEating behavioural factors: SnackingSnacking Portion sizePortion size Individual`s unique food preferences Individual`s unique food preferences Number of people with whom one eatsNumber of people with whom one eats

Molecules that Influence ObesityMolecules that Influence Obesity

• Afferent signals Afferent signals reach the hypothalamus: reach the hypothalamus: - - Neural SignalsNeural Signals - Hormones circulating in blood- Hormones circulating in blood - Metabolites- Metabolites

• Hypothalamus releases Hypothalamus releases efferent signals efferent signals (peptides) (peptides) that influence that influence appetite & energy expenditure appetite & energy expenditure

AdipocytesAdipocytesLEPTINLEPTIN

RESISTINRESISTINADIPONECTINADIPONECTIN

StomachStomachGHRELINGHRELIN

Circulating Circulating HormonesHormonesINSULINCCK

Nerves & CNSNerves & CNS NOREPINEPHRINEDOPAMINE SEROTONIN

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Hormones of Adipose TissueHormones of Adipose Tissue

Fat Cells Fat Cells (Adipocytes) (Adipocytes)

Store fatsStore fats&

Function as Endocrine Cells Function as Endocrine Cells

Release Many Regulatory MoleculesRelease Many Regulatory Molecules as as Leptin, Adiponectin & ResistinLeptin, Adiponectin & Resistin

LeptinLeptin

• Leptin is the hormone product of the Leptin is the hormone product of the gene obgene ob• Secreted by Secreted by fat cells fat cells (adipocytes)(adipocytes)• Produced Produced proportionallyproportionally to adipose mass to adipose mass• Acts on the hypothalamus Acts on the hypothalamus of the brain to regulate the amount of body of the brain to regulate the amount of body

fat through the control of fat through the control of appetite & energy expenditureappetite & energy expenditure• Leptin secretion is : Leptin secretion is : SuppressedSuppressed by starvation by starvation EnhancedEnhanced by well-fed state by well-fed state

LeptinLeptin (cont.)(cont.)

In In HumansHumans (in normal conditions) (in normal conditions), , leptin increases metabolic rate & leptin increases metabolic rate & decreases appetitedecreases appetite

In In Obese HumansObese Humans, , plasma leptin plasma leptin is is normal for their fat massnormal for their fat mass indicating the indicating the resistance to leptin resistance to leptin Researches Concluded that:Researches Concluded that: Hypothamic receptors for leptin is produced by Hypothamic receptors for leptin is produced by db genedb gene Mutations of db geneMutations of db gene produces leptin resistance (experimentally in rodents)produces leptin resistance (experimentally in rodents) BUTBUT not in most human obesity not in most human obesity

GhrelinGhrelin

• A peptide secreted primarily in the A peptide secreted primarily in the stomachstomach• The only known The only known Appetite-stimulating hormone Appetite-stimulating hormone in humansin humans Research:Research: Injection of ghrelin in the rodents:Injection of ghrelin in the rodents: Increases food intakeIncreases food intake Decreases energy expenditure Decreases energy expenditure Decreases fat catabolism Decreases fat catabolism

Metabolic Effects of Obesity:Metabolic Effects of Obesity:Metabolic Syndrome Metabolic Syndrome

(Insulin Resistance Syndrome or Syndrome X)(Insulin Resistance Syndrome or Syndrome X)

• Insulin ResistanceInsulin Resistance• HyperinsulinemiaHyperinsulinemia• Glucose Intolerance (& DM)Glucose Intolerance (& DM)• Dyslipidemia (Low HDL & Elevated VLDL)Dyslipidemia (Low HDL & Elevated VLDL)• HypertensionHypertension

WITH SIGNIFICANTLY INCREASED RISK OF DEVELOPING WITH SIGNIFICANTLY INCREASED RISK OF DEVELOPING DM & CARDIOVASCULAR DISORDERSDM & CARDIOVASCULAR DISORDERS

Men with the syndrome are 3 – 4 times more likely to die from Men with the syndrome are 3 – 4 times more likely to die from cardiovascular diseasecardiovascular disease

• Insulin resistance is the decreased ability of target tissues, such as liver, adipose Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulintissue & muscle to respond properly to normal circulating insulin

• Insulin resistance Insulin resistance increases with weight gain (overweight & obesity) & increases with weight gain (overweight & obesity) & diminishes with weight loss (controlling overweight & obesity)diminishes with weight loss (controlling overweight & obesity)

Fat accumulation (Fat accumulation (OBESITYOBESITY) causes insulin resistance ) causes insulin resistance as:as: - Substances produced by fat cells as - Substances produced by fat cells as leptinleptin & & resistinresistin may contribute to may contribute to development of insulin resistancedevelopment of insulin resistance - - Free fatty acidsFree fatty acids elevated in obesity is involved in insulin resistance elevated in obesity is involved in insulin resistance

Metabolic Effects of Obesity:Metabolic Effects of Obesity:

Insulin ResistanceInsulin Resistance

In early stages of insulin resistanceIn early stages of insulin resistancewith the absence of defect in -cell function

obese individuals can compensate for insulin resistance

by increasing levels of secretion of insulin from -cellsSo, glucose levels in blood remain within normal rangeSo, glucose levels in blood remain within normal range

With time (late stages)With time (late stages)-cells become dysfunctional

(due to fat cells substances , FFA & hyperglycemia)

So-cells fail to secrete enough insulin leading toIncreased blood glucose levels (hyperglycemia)Increased blood glucose levels (hyperglycemia)

Metabolic effects of obesityMetabolic effects of obesity::

Insulin Resistance & Hyperglycemia Insulin Resistance & Hyperglycemia (cont.)

Metabolic Effects of Obesity:Metabolic Effects of Obesity:

DyslipidemiaDyslipidemia

Insulin resistance in adipose tissuesInsulin resistance in adipose tissues causes increased activity of hormone-sensitive lipase (deactivated with insulin) resulting

in increased free fatty acids free fatty acids released in blood

In the liverliver, free fatty acids are converted to cholesterol & triacylglycerol

Excess cholesterol & triacylglycerol are released as VLDLVLDL with

Increased Blood Triacylglycerol & HyperchlosterolemiaIncreased Blood Triacylglycerol & Hyperchlosterolemia

with increased risk of with increased risk of

Coronary Heart Diseases (CHD)Coronary Heart Diseases (CHD)

Metabolic Effects of Obesity:Metabolic Effects of Obesity:

DyslipidemiaDyslipidemia

Obesity & HealthObesity & Health

Obesity is Obesity is a Risk Factor for Many a Risk Factor for Many Chronic DiseasesChronic Diseases

Type 2 DMType 2 DM HypercholesterolemiaHypercholesterolemia

High plasma level of triacylglycerolHigh plasma level of triacylglycerol HypertensionHypertension

Coronary Heart DiseasesCoronary Heart Diseases Some CancersSome Cancers

GallstonesGallstones ArthritisArthritis

GoutGout

Biochemical Principles of Biochemical Principles of Weight ReductionWeight Reduction

GOALS of weight management in obese patients:GOALS of weight management in obese patients:

• To To induce negative energy balance induce negative energy balance to reduce body weightto reduce body weight by decreasing caloric intake and/or increase energy by decreasing caloric intake and/or increase energy

expenditureexpenditure

• To To maintainmaintain a lower body weight over a longer term a lower body weight over a longer term

Weight Reduction:Weight Reduction:

1- Physical Activity1- Physical Activity

BenefitsBenefits:• Increases cardiopulmonary fitness Increases cardiopulmonary fitness • Reduces risk of cardiovascular diseases Reduces risk of cardiovascular diseases (independent on weight loss)(independent on weight loss)

Combination of Combination of Caloric Restriction + Exercise + Behavioural Treatment Caloric Restriction + Exercise + Behavioural Treatment

is expected to is expected to Reduce Reduce 5 – 10 % 5 – 10 % of weight over a period of 4-6 monthsof weight over a period of 4-6 months

Physical activity is essential for maintaining weight reduction Physical activity is essential for maintaining weight reduction

Weight Reduction:Weight Reduction:

1- Caloric Restriction1- Caloric Restriction

• 1 pound of adipose tissue ( 1 pound of adipose tissue ( about 0.5 kgabout 0.5 kg) corresponds to about ) corresponds to about 3500 Kcal3500 Kcal

• Ineffective for a long term for many obese individuals Ineffective for a long term for many obese individuals • More than 90% regain the lost weight after suspension of dietingMore than 90% regain the lost weight after suspension of dieting

• Benefits of caloric restrictionBenefits of caloric restriction Reduction of 10% of weight over a 6-month period often:Reduction of 10% of weight over a 6-month period often: - Reduces Blood Pressure - Reduces Blood Pressure - Reduces Lipid levels - Reduces Lipid levels - Enhance Control of Type 2 DM- Enhance Control of Type 2 DM

Weight Reduction:Weight Reduction:1- Pharmacological Treatment 1- Pharmacological Treatment

• For BMI 30 or more:For BMI 30 or more: 1- Sibutramine:

Appetite suppressant inhibits serotonin & norepinephrine reuptake

2- Orlistat: 2- Orlistat: lipase inhibitor that inhibits gastric & pancreatic lipaseslipase inhibitor that inhibits gastric & pancreatic lipases It inhibits digestion & hence absorption of about 30% of It inhibits digestion & hence absorption of about 30% of diet fat.diet fat.

Weight Reduction:Weight Reduction:

1- Surgical Treatment1- Surgical Treatment

• AimsAims at reducing food consumption at reducing food consumption• Only Only indicatedindicated for severely obese patients for severely obese patients