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.