Leptin
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Transcript of Leptin
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Leptin
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Lower Fat
Low Leptin
Reduces metabolismandstimulatesappetite
Binds toreceptorin brain
High Fat
High Leptin
Unbindsfromreceptorin brain
Stimulatesmetabolismand reducesappetite
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Leptin and Body fat positivelycorrelated in humans(but correlation not super tight)
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Who has leptin?Southern blotfrom Zhang’soriginal paper (1994- 8000 papers since then)
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So-it regulates body fat (adiposity)-whatelse does it do?
Regulates body temperature and metabolic rate.
Leptin injections increasebody temp 5oC andincrease metabolic rate20% in mice.
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What else does it do?
Immune function-Starving mammals tend to have compromised immune function. Leptininjections 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 30’s)
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Angiogenesis-
High leptin stimulates growth of blood vessels
Stain is antibodythat recognizes leptinreceptors-This shows they are present in endothelialcells
# of Endothelial cells increases with leptininjections
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Leptin now thought to have evolved as a way to sensestarvation, 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 anythingand is only foundin brain-others found in manytissues
These are the varioustypes of mutantleptin 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
10-68, 396
Interferon is theligand in this diagram,but leptin is thoughtto work the sameway
JAK=janus kinaseSTAT=signal tranducersand activators of transcription
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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 as‘disappointing’ by many (stock brokers).
Come up with a reasonable hypothesis as to why leptin injectionswould not cure obesity in humans.
Let’s 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.