2. INTRODUCTION
• obesity is increased body weight due to excess deposition of fat.
• Global scenario .
• Body can deal with excess fat in three ways.
• Adipose tissue has important endocrine functions.
• It is measured by BMI = weight in kg
(height in meter )2
provides a relative weight adjusted for height.
• Anatomical distribution in fat deposition can be measured by waist-
to-hip ratio.
upper abdominal obesity- men >1.0,
women >o.8
lower abdominal obesity- men<1.0
women <0.8
3.
4.
5. INTRODUCTION cont…
• With abdominal obesity , there Is increased release of FFT and
secretion of proinflammatory cytokines , such as interleukin 6 ,
from adipose tissue which are enter into portal circulation and
causes hyperlipidemia and increased insulin resistance.
• On the otherhand FFT from lower body adipose depot enter the
general circulation, where they can be oxidized in muscle and
therefore reach in liver in lower concentration.
6. The discovery of leptin
• A strain of mice gene called obese, or OB gene, was first
discovered in 1950 by researchers at The Jackson Laboratory.
A recessive mutation (ob)causes these mice to be massively
obese: they weigh three times as much as normal mice, and
their appetite is insatiable.
• The existence of leptin hormone that functions to control
appetite and feeding behavior, was hypothesized by D.L.
Coleman in 1978, almost 20years before advances in
molecular biology allowed for the isolation of the hormone
and the identification of its associated gene.
• Coleman derived his hypothesis from the interpretation of
experiments he performed with mice harboring a genetic
mutation called db.
7. • Mice with this mutation, called db/db mice, are obese,
diabetic, and hyperphagic (exhibit uncontrolled eating).
• When Coleman connected the circulatory system of a lean
mouse with the circulatory system of a db/db mouse (referred
to as “parabiosis”), the lean mouse eventually died of
starvation,
• while the db/db mouse lived on, unaffected.
• In order to explain this result, Coleman hypothesized that the
db/db mice produce a circulating molecule that, when
introduced to the lean mouse via parabiosis, causes the lean
mouse to cease eating, eventually leading to death by
starvation.
8. • Subsequent research confirmed Coleman’s hypothesis: db/db
mice produce abnormally large quantities of leptin, and the
introduction of these large quantities of hormone to the
circulatory system of lean mice precipitates their starvation
and eventual death
• In addition to his studies with the db mutation, Coleman also
studied mice with a different genetic mutation, occurring on a
different chromosome, called OB.
• Mice with this mutation, called ob/ob mice, are obese,
diabetic, and hyperphagic, just like db/db mice.
9. Results of three parabiosis experiments: db/db with lean, db/db with
ob/ob, and lean with ob/ob.
Experiment 1 db/db: no change observed
Lean: hypophagia,
hypoinsulinemia, and
hypoglycemia. Death by starvation.
Experiment 2 db/db: no change observed
ob/ob: hypophagia,
hypoinsulinemia, hypoglycemia,
and reduction in adipose tissue
mass. Death by starvation
Experiment 3 Lean: no change observed
ob/ob: normalization of eating
behavior, blood glucose levels, and
circulating insulin levels. Reduction
in adipose tissue mass.
10.
11. Leptin
• A peptide hormone.
• 167 aa residue
• 16 kd
• OB Gene encodes leptin ,Located in chr no 7 in
human.
• Secreted dominantly by adipocytes and little amount
intestinal wall, placenta etc.
• Shows diurnal variation.
• Discovered by Dr. Jeffrey Friedman’s team on 1994.
• Derived the name from Greek word Leptos- thin
• Product of OB gene.
• DB gene encodes leptin receptor.
12. Leptin synthesis
• White adipose tissue (WAT) is the main site of leptin synthesis,
but it is now evident that it is also produced in other tissues ,
including placenta, ovaries, skeletal muscle and stomach and
brown adipose tissue as well.
• Transcription of the leptin gene in mice yields a mRNA of ~3.5
kb that is expressed primarily in adipose tissues, but recent
studies have confirmed that some other tissues also express
leptin.
• In humans, leptin is encoded by a gene located in human
chromosome 7q31.3 and is similar to that in rodents.
13. Leptin synthesis cont…
• Leptin is translated as a 167 amino acid protein with
an amino-terminal secretory signal sequence of 21
amino acids.
• The signal sequence is functional, and results in the
trans-location of leptin into microsomes with the
subsequent removal of the signal peptide.
• Therefore, leptin circulates in the blood as protein of
146 amino acid residues
14. Structure of leptin
4 antiparallel helices each about
5-6 turn long
Two long loops connecting
helices A-B and C-D, shorter loop
connecting helices B-C.
Resembles member of helical
cytokine family
Two cysteine residues at the 96
and 146 position
Disulphide bridge and kink in the
D-helix are a essential for proper
folding and receptor binding.
18. Neuronal Way of regulates thermogenesis
by action of leptin?
19.
20. Leptin recepters
• Leptin acts on receptors in the lateral hypothalamus to inhibit
hunger and the medial hypothalamus to stimulate satiety.
• In the lateral hypothalamus, leptin inhibits hunger by
counteracting the effects of neuropeptide Y.
• In the medial hypothalamus, leptin stimulates satiety by
promoting the synthesis of α-MSH, a hunger suppressant .
• Thus, a lesion in the lateral hypothalamus causes anorexia
(due to a lack of hunger signals) and a lesion in the medial
hypothalamus causes excessive hunger (due to a lack of
satiety signals)
25. Clinical utility
• OB gene mutant/ defective ,Leptin deficient obese
persons are benefitted with leptin injection.
• DB gene mutant/ defective obese persons are
benefitted with combined leptin and amylin therapy.
Weight reduction as much as 13%.
• Leptin increases insulin sensitivity to receptor but
high level causes resistance.
• Leptin resumes fertility in leptin deficient.
