Obesity and Leptin

Presented by Dr.Pulak Ranjan Das

2nd year PGT Dept.of Biochemistry , BMC&H

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

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.

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.

• 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.

• 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.

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 observedLean: hypophagia, hypoinsulinemia, and hypoglycemia. Death by starvation.

Experiment 2 db/db: no change observedob/ob: hypophagia, hypoinsulinemia, hypoglycemia, and reduction in adipose tissue mass. Death by starvation

Experiment 3 Lean: no change observedob/ob: normalization of eating behavior, blood glucose levels, and circulating insulin levels. Reduction in adipose tissue mass.

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.

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.

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

Structure of leptin4 antiparallel helices each about

5-6 turn longTwo 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.

Regulations of food intake and energy expenditure

Leptin stimulates production of anorexigenic peptide hormones

Neuronal Way of regulates thermogenesis by action of leptin?

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)

How leptin act over the receptor ?

Jak-stat mechanism of leptin signal transduction in hypothalamus.

Serum leptin detection• Serum leptin Can be detected by ELISA , • HPLC method.

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.

Thank you