BIOKIMIA OBESITAS

ANNISA HANIFWATI
 Referensi :
- Clinical Biochemistry review Vol 25, Aug 2004
- Textbook of Biochemistry Illustrated Review
Fifth edition, Lippincotts 2010
- Biochemistry of Leptin, Shaliana, National
Dairy Research India
- The Biochemistry of Obesity, Rick Voake MD
- Medical Biochemistry 4th ed,2002,NV
Bhagavan
 THE CLINICAL BIOCHEMISTRY OF
OBESITY
ABSTRACT
OBESITY:
- RESULT OF EXCESSIVE ENERGY INTAKE COMPARE TO ENERGY USAGE (
DECREASED PHYSICAL ACTIVITY)
- PHYSICAL CONSEQUENCES OF OBESITY : ARTHRITIS, INSULIN RESISTANCE,
DIABETES, FATTY LIVER, CAD, HYPERTENSION, PCOS
- PATOPHYSIOLOGICAL MECHANISME : COMBINATION OF TOXIC METABOLIC
EFFECTS OF FFA & ADIPOKINES
 INTRODUCTION
OBESITY : INCREASED ADIPOSE TISSUE MASS
ADIPOSE TISSUE :
- STORAGE TISSUE FOR TRIACYLGLICEROL
- AN ENDOKRIN ORGAN, RELEASING ADIPOKINES
. DEFINITION OBESITAS
WHO GUIDELINE 1985: BMI>25 : OVERWEIGHT
>28,5 : OBESE (WOMEN)
>30 : OBESE (MEN)
BMI: calculated as weight (kg) divided by height squared (m2)
 ACQUIRES CAUSE OF OBESITY
- CHILDREN : INCREASED ENERGY INTAKE (SUGAR), DECREASED PHYSICAL
ACTIVITY
- CUSHING SYNDROME : TRUNCAL / VISCERAL OBESITY
- HYPOTHYROIDISME : RARE CASE OF OBESITY, WEIGHT GAIN IS DUE TO
WATER RETTENTION, WHICH IS REVERSIBLE AFTER THYROID HORMON
THERAPY

- NORMALLY :
SIGNAL FROM THE GUT & ADIPOSE TISSUE ARE INTEGRATED IN HTE CNS
TO AFFECTS APPETITE & ENERGY HOMEOSTASIS & LIMIT WEIGHT GAIN
- PATHOLOGICAL OBESITY:
FAILURE OF HOEMOSTATIC MECHANISME
 GENETIC CAUSE OF OBESITY
- THRIFTY GENE HYPOTHESIS : CERTAIN POPULATIONS MAY HAVE GENES
THAT DETERMINE INCREASED FAT STORAGE, IN A MODERN
ENVIRONMENT RESULT IN OBESITY & DM TYPE 2
- SINDROMA PRADER-WILLI, SINDROM ANGELMAN, SINDROM WILSON-
TURNER

. LEPTIN ASSOCIATED GENES

- LEPTIN SECRETED FROM ADIPOCYTES INTO THE CIRCULATION TRANVERSE
INTO THE CNS
- BINDS TO LEPTIN RECEPTOR IN HIPOTALAMUS
- LEPTIN STIMULATES PRODUCTION OF ALFA MSH & ACTH. MSH BIND TO
MELANOCORTIN RESEPTOR IN HIPOTALAMUS, CAUSE DECREASE FOOD
INTAKE
- MUTATION OF SISTEM ( LEPTIN, RESEPTOR, MSH), CAUSE OBESITY (RARE/
UNCOMMON)
- OBESITY : USUALLY HIGH LEPTIN, BUT LEPTIN RESISTEN, CAUSE
DEFICIENCY LEPTIN

. OBESITY & INSULIN RESISTANCE :

- OBESITY & DM TYPE 2: INSULIN RESISTEN
- DM TYPE 2 : OVERWEIGHT, OBESE > 90%
- PREECED THE ONSET DM TYPE 2: WEIGHT GAIN & INSULIN RESISTEDM
- CURRENT THEORIES : DM TYPE 2 DEVELOP WHEN PANCREATIC BETA CELL
OUTPUT CAN NO LONGER SATISFY THE DEMAND, IMPOSED BY INCREASED
INSULIN RESISTEN
 FFA PARADIGMA LINKING OBESITY TO INSULIN RESISTANCE
- ELEVATED CELLULER LEVEL OF FFA : PRODUCE INSULIN, RESISTANCE IN
SKELETAL MUSCLE&LIVER, REDUCE BETA CELL FUNCTION, CAUSE
LIPOTOXICITY

. CAUSATIVE FACTOR INVOLVED IN HEPATIC INSULIN RESISTANCE :

- HEPATIC FFA
- TRIGLYCERIDE ACCUMULATION

. INSULIN RESISTENT MUSCLE CHARACTERISED BY :

- LOWERED ABILITY TO OXIDISE FFA
 IMBALANCE BETWEEN FFA UPTAKE- OXIDASI
- PROMOTING ACCUMULATION OF LIPID & TRIACYLGLYCEROL IN SKELETAL
MUSCLE, CAUSE INSULIN RESISTANCE

. FFA : - BLOCK INSULIN SIGNALLING PATHWAY

- LEAD INSULIN RESISTEN

. ADIPOKINE PARADIGMA LINGKING OBESITY TO INSULIN RESISTAN

- ADIPOSE TISSUE : AN ENDOKRINE ORGAN
- ADIPOKINES : ADIPOSE TISSUE-DERIVED HORMONES&INFLAMMATORY
CYTOKIN
- DYSFUNCTION OF ADIPOSE TISSUE CAUSING SYSTEMIC INSULIN RESISTEN
 LEPTIN
- DISCOVERD IN 1994
- LEPTIN : DECREASE NEUROPEPTIDE Y IN HIPOTALAMUS, SHOULD
SUPPRESS APPETITE
- LEPTIN PRODUCE BY ADIPOSE TISSUE, PLACENTA, BONE MARROW,
SOMACH, MUSCLE, BRAIN
 Leptin
Leptin:
encoded by the OB (obese gene)
protein is 167 amino acid residues long
generated mainly in adipose tissue
messenger reduce fuel intake
increases heart rate, blood pressure, thermogenesis
acts on leptin receptors

Leptin receptor
encoded by the DB (diabetic gene) in mice
located mainly in the hypothalamus
also expressed in cells of the adrenal cortex & beta-
cells
Theodor
binding of hormone to receptor reduces appetite 11
Hanekamp 2003
 Leptin deficient mice
Leptin deficient homozygous mice (ob gene)
behave like mice that are constantly starving
are 3 times bigger than normal
cant stay warm
resemble diabetic mice(DB)
are insulin-resistant
db/db mice are obese and diabetic
ob/ob

OB/ob or OB/OB
Theodor Hanekamp 2003 12
 Leptin cascade
Appetite suppressing
neuropeptides
(a -MSH) a-melanocyte-stimulating
hormone
(POMC)Proopiomelanocortin
(CRH) Corticotropin releasing hormone
(CART) Hypothalamic peptide
Appetite stimluating
neuropeptides
(NPY) Neuropeptide Y

Theodor Hanekamp 2003 13

 BIOCHEMICAL MEDIATOR OF OBESITY

The regulation of intake & expenditure is

achieved by coordinating the effect of
endocrine mediators & neural signal that arise
from adipose tissue, endocrine gland,
neurological & gastrointestin system. All of the
information finally is integrated by the CNS
 One of the most significant mediator of the
energy store in the adipose tissue is leptin
(from the Greek), leptin meaning thin. Leptin
is a protein of 167 amino acid residues that is
synthesized in adipocytes. Its syntesis is
increased by insulin, glucocorticoid, &estrogen
& is decreased by beta adrenergic agent. The
role of leptin in obesity comes from studies in
rodent.
 In genetically obese mice (ob/ob) the
observed gross obesity is due to abscense of
leptin production in adipocytes. Leptin action
on energy metabolisme is mediated by
receptor in many cells and it bind spesifically
to a receptor in the hypotalamus.
The action of leptin involves at least 2
pathways.
 During starvation &weight loss, adipose tissue
is decreased, low level of leptin. Low leptin
leads to production of neuropeptide Y, which
is syntesized in the arcuate nuclues of
hypotalamus & transported axonally to the
paraventricular nucleus. Neuropeptide Y binds
to its reseptor & functions as a potent
appetite stimulant.The effect is increased
appetite, decrease energy expenditure,
increase parasympathetic activity
 An opposite, when the leptin level rise,
mediated by melanocyte-stimulating hormon
(MSH), that bind melanocortin 4 receptor
(MC4R). MSH binding to MCR4 initiates
biological response: decrease appetite,
increase energy expenditure & increase
symphatetic activity
 Most obese human, plasma level of leptin are
high due to excess adipose tissue. Inspite of
abundant leptin, there is continued overeating
Inheritage obese disorder : hyperphagia lead
obesity, hypogonadisme, mental retardation
(Willi Prader syndrom, 1 of 10.000-20.000
birth). Delete in chromosom 15
 THE BIOCHEMISTRY OF OBESITY

The Hypothalamic-Leptin Axis

Feedback system
Allows the fat cells to tell the brain to quit
seeking more food when too much fat is
present.
Allows the brain to adjust the metabolic rate
to control energy use.

Lustig, Ped Annals, 35:12 Dec 2006

 Physiological effects of Leptin
Regulation of food intake ,energy
expenditure and body weight .
Thermogenesis .
Reproductive function .
Supressed bone formation .
Directly act on the cells of liver and muscles
.
Related to inflammatory response .
Contribute to early hematopoiesis.
 The Hypothalamic-Leptin Axis
How it works:
When excess fat builds up in the fat cell, leptin
is produced and enters the bloodstream.
Leptin receptors in the hypothalamus are
triggered.
This shifts the hypothalamus into Spend
Energy mode.
Leptin changes SLOWLY (days to weeks)
Lustig, Ped Annals, 35:12 Dec 2006
 Spend Energy Mode
Appetite reduction (Dont Increase TSH to increase
need to waste time looking thyroid output and increase
for more food) baseline energy expenditure
Increase sympathetic tone to Beta-adrenergic stimulus to
skeletal muscle increasing fat cells increases lypolysis
ATP and mitochondrial (Break out stored energy for
proteins (Muscles are
prepared to function immediate use)
optimally)

Lustig, Ped Annals, 35:12 Dec 2006

 Conserve Energy Mode
Appetite increases (Need
to seek more food for
energy)
Decrease sympathetic and
increase vagal tone to slow
down muscle function
Increase fat absorption by
fat cells
Lustig, Ped Annals, 35:12 Dec 2006
Vagus increases
peristalsis and insulin
production (for food
processing)
Vagus nerve also slows
heart rate and myocardial
oxygen consumption
 What if leptin feedback is blocked?
Hypothalamus is tricked into thinking that
there is no leptin being released from fat cells.
It then sends Orexin-A all over your brain,
making you think you are starving.
The hypothalamus is stuck in conserve
energy mode, increasing appetite, slowing
down metabolic rate, increasing fat storage.
Your brain is constantly starving even
though the fat cells are busting at the seams!
 Orexin-A (hypocretin-1)
Small peptide hormone released by the
hypothalamus to act on the rest of the brain.
It signals hunger, after the hypothalmus is
stimulated by ghrelin from the stomach
It also signals wakefulness, so that your brain
stays awake long enough to seek food, and
not to hibernate!
Another reason obese children dont sleep
well
 Energy in = Energy out ???
Obese children are leptin resistant (leptin
receptors are blocked)
They are stuck in Conserve Energy mode
Their brains are starving, so they are
constantly seeking more food
Yet very little of that energy is available for
activity, since it is routed away into the fat
cells.
 What blocks leptin?
Brain damage to the leptin receptor area:
hypothalamic obesity syndrome
Insulin excess blocks leptin receptors
(Fructose is what leads to insulin excess)
 What blocks leptin?
Brain damage to the leptin receptor area:
hypothalamic obesity syndrome
Insulin excess blocks leptin receptors
(Fructose is what leads to insulin excess)
 Insulin excess blocks leptin

Lustig, Ped Annals, 35:12 Dec 2006

 Insulin excess blocks leptin
Insulin receptors in the brain share the same
substrate as leptin receptors
When there is excess insulin, it hogs all the
substrate, leaving none for leptin to use.
Leptin attaches to the receptor, but nothing
happens.
 In the hyperinsulin state

Even high levels of leptin have no effect on

the hypothalamus
Known as leptin resistance
Occurs in a large percentage of overweight
children and adults
 CAUSA HYPERINSULINEMIA :
- HIGH FAT DIET
- LOW FIBER DIET
- SLEEP DEPRIVATION
- HIGH FRUCTOSA
 Fructose:
A major cause of hyperinsulinemia
Fructose is absorbed from the intestine and
enters the liver without insulin regulation,
AND it does not suppress ghrelin (hunger
hormone).
It is then converted into acetyl-CoA, which
floods the Kreb cycle, forcing excess
production of FFA, triglycerides and VLDL
lipoproteins.
 Review:

What fructose becomes in your liver

FFA (free fatty acids, the building blocks of all
lipids)
VLDL lipoproteins and triglycerides (the nasty
lipids most associated with cardio- vascular
disease)
Uric acid (oxidative stress, vascular
inflammation)
 Fiber is also a factor
Fiber adds bulk to foods, so the stomach turns
off ghrelin sooner
Fiber slows absorption of sugar in the gut
Fiber binds to bile acids, reducing fat
absorption from the gut
Fruits and veggies are a good source
 Fructose:
A major cause of hyperinsulinemia
All this excess fat production leads to fatty
liver which causes hepatic insulin resistance
Fructose also activates the enzyme jnk-1
which causes hepatic inflammation, and more
insulin resistance
Faulty feedback to the liver results in massive
insulin production, leptin resistance, and
obesity
 Fiber is also a factor
Fiber adds bulk to foods, so the stomach turns
off ghrelin sooner
Fiber slows absorption of sugar in the gut
Fiber binds to bile acids, reducing fat
absorption from the gut
Fruits and veggies are a good source
Other symptoms of fructose poisoning
Diabetes (hyperinsulin state, insulin
resistance)
Cardiovascular disease
Hypertension (renovascular damage)
Fatty liver
Hyperlipidemia
Increased BMI from excess lipid stored in fat
cells
Sound familiar?
 Metabolic Syndrome = Fructose Poisoning

With higher BMI, other symptoms can evolve

PCOS (polycystic ovary syndrome)
Acanthosis nigricans
Diabetic complications
Elevated CRP, endothelial damage
How leptin works ?
 Role of leptin in regulation of food
intake and body weight
Decrease hunger and food consumption -
inhibition of neuropeptide Y synthesis .

Food intake linked to its ability to regulate the

neuroendocrine system .
 Neuropeptide Y
36 a.a residue produce in the arcuate nucleus of
the hypothalamus . Rich in tyrosine residues .

Appetite stimulating hypothalamic peptide

Contd.
Found in many organ, high level of NPY are found in
brainstem and hypothalamus .

Stimulates leptin production in adipose tissue by

increasing food intake and insulin secretion.

Action through the parasympathetic nervous system.

 Role of leptin in lipid metabolism
Inhibits intracellular lipid concentration

Activate 5 AMP-activated protein kinase (AMPK)

Inhibits acetyl coenzyme-A carboxylase (ACC)

Increase in fatty acid oxidation and reducing the

fat tissue in muscles and liver
.
Increase insulin sensitivity .
 Inducers and suppressers of leptin expression
Inducers Effect Species
Feeding + Rodent + man
Glucocorticoids + Rodent + man
Insulin + Rodent
C or + Man
Cytokines + Rodent
Obesity + Rodent + man
Fasting - Rodent + man
Pertussis toxin - Rodent
-receptor antagonists - Rodent
Thiazolidinediones - Rodent
cAMP - Rodent
 Feedback loop
Food intake trigger the output of glucocorticoids and
insulin

Favour fat accumulation & increase leptin

Leptin travels to hypothalamus

Regulate body mass & control body energy intake ,

energy expenditure

NPY also regulate body fat mass

 Obesity
Main focus of leptin research.

Dramatic effects on obesity in mice.

In human a body mass index over 27.3 for man &

27.8 for women.

Hypothalamic insensitivity to leptin fundamental

mechanism of obesity.
 Leptin resistance
Mutation of the gene for leptin receptors in
the brain

Post receptor abnormalities in leptin signal

transduction

Impaired leptin transport across blood- brain

barrier
 What about humans:
Human fat cells also manufacture leptin protein
(167 a.a )

Mutation in gene for leptin or its receptor are

rarely found in obese people

High blood conc. leptin indicates leptin resistance

Extreme obesity in 5 members of two families

that are homozygous for mutation in their leptin
gene like ob/ob mice.
Contd.
Extreme obesity among three members of a family
homozygous for mutation in leptin receptor gene-like
db/db mice.

Only moderate obesity in people heterozygous for leptin

gene.

Recombinant human leptin available.

The 16 september 1999 issue the New England Journal of

Medicine reports- 9 year old girl homozygous for frame
shift mutation leptin gene.
Contd.

Factor in obesity - -3 adrenoreceptor

Defect contribute leptin

resistance/leptin expression

A paradox exists-comparison between

mouse & human research cannot be
made
 Future prospects
More focus on leptin receptor & involvement
in leptin resistance

Relation to reproduction

Mechanisms involved in regulation of leptin