PPoint Lec 17

Leptin

High Leptin

Binds to receptor in brain

High Fat

Stimulates metabolism and reduces appetite

Reduces metabolism and stimulates appetite

Lower Fat Unbinds from receptor in brain

Low Leptin

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

Who has leptin? Southern blot from Zhang’s original paper (19948000 papers since then)

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.

What else does it do? Immune functionStarving mammals tend to have compromised immune function. Leptin injections reverse that (even though they are still starving). Bone DensityHigh leptin inhibits the activity of osteoblasts (cells that build bone)leptin-deficient mice have thicker bones ReproductionVery 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)

AngiogenesisHigh leptin stimulates growth of blood vessels

Stain is antibody that recognizes leptin receptorsThis shows they are present in endothelial cells # of Endothelial cells increases with leptin injections

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

It, of course, gets more complicated… Various types of leptin receptorsonly 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

Once leptin binds to its receptor, it activates JAK/STAT pathways, which subsequently turn the right genes on/off JAK=janus kinase STAT=signal tranducers and activators of transcription 10-68, 396 Interferon is the ligand in this diagram, but leptin is thought to work the same way

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 injections would 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.