BIOCHEMISTRY OF LEPTIN Shalini Jain and Hariom Yadav Animal Biochemistry Division Natioanal Dairy...
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Transcript of BIOCHEMISTRY OF LEPTIN Shalini Jain and Hariom Yadav Animal Biochemistry Division Natioanal Dairy...
BIOCHEMISTRY OF LEPTIN
Shalini Jain and Hariom Yadav
Animal Biochemistry Division
Natioanal Dairy Research Institute
Karnal-132001 (Haryana), India
How leptin is discovered Three theories evolved : Thermo regulation influenced the VMH Glucostatic theory – plasma glucose regulated over all
energy stores .
Lipostatic theory – product of fat metabolism that circulated in the blood and interacted with the VMH
Factor was discovered in 1994 by Dr. Jeffrey Friedman's team .
Factor was termed ‘Leptin’.
Leptin (OB)
16 KDa protein encoded by ob gene.
Expressed & secreted by – adipocytes, placenta, gastric epithelium.
Directly proportional to the total amount of fat in the body.
mice are homozygous for single gene mutation.
ob/ob –protein hormone leptin
db/db –receptor for leptin .
High degree of homology
Leptin structure 146 a.a residue non glycosylated polypeptide
Member of helical cytokine family
Primary structure of leptin
Contd.
folding pattern compatible with the helical cytokines
Mutant form of leptin E-100, sustitution at 100 position Glu – Trp.
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.
Small helical segment E
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.
Contd.
Act as binding protein. A tail with 34 a.a residues – OB-Ra
form . A tail of 32 & 40 a.a –OB-Rc form and OB-Rd
form. OB-Re form terminate before transmembrane
segment and this represent a soluble receptor In db/db mice gene under go abnormal splicing-
truncated receptor. OB bind with OB-R with high affinity(Kd = 250-
700 pM).
Signalling Pathway of Leptin Action
Physiological effects of LeptinRegulation 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.
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 Y36 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 thermogenesis
Role of leptin in reproduction
Fertility influenced by stored body fat
Leptin signals the onset of puberty .
Regulates hypothalamic- pituitary – ovarian function .
Contd.
Role of leptin in lipid metabolismInhibits 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 .
Inflammatory responseLong form of leptin receptor is expressed by T- lymphocytes, bone marrow, spleen.
Leptin released in response to inflammatory cytokines attenuating its response and hence. modulating inflammatory response.
Stimulates the expression of POMC -processed to -MSH.
Against the auto aggressive effects of the immune system.
Regulation of leptin expression
Two transcription factors PPAR and C/EBP control the adipocyte differentiation
C/EBP promotes the leptin expression. PPAR decrease leptin expression
Regulated by environmental and hormonal factors
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 resistanceMutation 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.
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.
Contd.
Factor in obesity - -3 adrenoreceptor
Defect contribute leptin resistance/leptin expression
A paradox exists-comparison between mouse & human research cannot be made
Leptin research results
Weight lost with mutated ob gene
Not effective without genetic defect ob gene
More obese less sensitive high level leptin
Future prospects
More focus on leptin receptor & involvement in leptin resistance
Relation to reproduction
Mechanisms involved in regulation of leptin
Conclusion
Much more research needs to be done to fully realize the potential of leptin in the body
When the medical community does learn more about leptin’s control & regulation,it will surely have a profound impact on the treatment of obesity , infertility