Leptin. Leptin and Body fat positively correlated in humans (but correlation not super tight)

Leptin

Lower Fat

Low Leptin

Reduces metabolismandstimulatesappetite

Binds toreceptorin brain

High Fat

High Leptin

Unbindsfromreceptorin brain

Stimulatesmetabolismand reducesappetite

Leptin and Body fat positivelycorrelated in humans(but correlation not super tight)

Who has leptin?Southern blotfrom Zhang’soriginal paper (1994- 8000 papers since then)

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.

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)

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

Leptin now thought to have evolved as a way to sensestarvation, and respond by ramping down all the “frills”

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

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

Maybe leptin is not the magic bullet…

Many other peptides active in appetite control

The agouti mouse always making MCH

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.