Leptin

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Leptin
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Leptin and Body fat positively correlated in
humans (but correlation not super tight)
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Who has leptin? Southern blot from
Zhangs original paper (1994- 8000 papers
since then)
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So-it regulates body fat (adiposity)-what else
does it do? Regulates body temperature and
metabolic rate.
Leptin injections increase body temp 5oC
and increase metabolic rate 20 in mice.
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What else does it do?
Immune function- Starving mammals tend to have
compromised immune function. Leptin injections
reverse that (even though they are still
starving). Bone Density- High leptin inhibits
the activity of osteoblasts (cells that build
bone)- leptin-deficient mice have thicker
bones Reproduction- Very thin mice have low
levels of leptin, and do not enter puberty.
This can be reversed with leptin injections.
Also-humans (very few) with mutations in leptin
are grossly obese and have never entered puberty
(even into their 30s)
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Angiogenesis- High leptin stimulates growth of
blood vessels
Stain is antibody that recognizes
leptin receptors- This shows they are present in
endothelial cells
of Endothelial cells increases with
leptin injections
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Leptin now thought to have evolved as a way to
sense starvation, and respond by ramping down all
the frills
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It, of course, gets more complicated
Various types of leptin receptors- only Ob-Rb
(long form) seems to do anything and is only
found in brain -others found in many tissues
These are the various types of mutant leptin
receptors found
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Once leptin binds to its receptor, it activates
JAK/STAT pathways, which subsequently turn the
right genes on/off
JAKjanus kinase STATsignal tranducers and
activators of transcription
10-68, 396 Interferon is the ligand in this
diagram, but leptin is thought to work the
same way
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Maybe leptin is not the magic bullet Many other
peptides active in appetite control
The agouti mouse always making MCH
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Group Exercise 17
Amgen is currently undergoing phase II clinical
trials with a second generation version of
human recombinant leptin. Clinical trials with
normal HRL were described asdisappointing by
many (stock brokers). Come up with a
reasonable hypothesis as to why leptin
injections would not cure obesity in
humans. Lets say leptin will work, and high
doses make you slim and trim. What are the
potential side-effects of high doses of
leptin? Try this yourself for a minute, then
discuss it in small groups.