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Leptin tolerance

Posted by Paul

Leptin is our new friend that keeps making the news. It seems to be pivotal in fat metabolism.

The new findings more or less confirm what was suspected before. Obesity is directly linked with diminished sensitivity to the hormone leptin. Further, the *outstanding* good news is:

"Our data indicate that the increased leptin levels seen with mild

to moderate obesity are not genetically determined," Dr. Tapani Ronnemaa

Dr. Ronnemaa conducted a study of identical twins, where one twin was substantially more obese than the other (40 lbs on average). The heavier twins had leptin levels up to three times that of their non-obese sibling.

What does this mean? BEHAVIOR and LIFESTYLE are the reason for obesity, not genetic determinism!

Ref: Annals of Internal Medicine (1997;126:26-31)

Another recent paper describes the mechanism of leptin tolerance in obese mice. These mice were found to produce a peptide (short protein fragment) which blocks a brain receptor. This receptor, melanocortin-4 (MC4), apparently is the signalling junction for hunger or satiety. If the receptor is unblocked, rising leptin levels will stimulate it, and the response will be a deactiviation of hunger. If the MC4 receptor is blocked, the animal will keep eating and never stop feeling hungry, and will become a REALLY BIG MOUSE.

Ref: Nature (1997;385:165-168)

Now, to bring it all home, we need to consider what we learned just before Thanksgiving. Leptin interferes with insulin function, and leptin seems to have evolved as more of a safety against starvation than against obesity.

Let's put the pieces together.

1. Leptin levels rise with food intake.
2. Leptin antagonizes NPY, the hunger signal.
3. Over time, high food intake causes production of the peptide which blocks the MC4 receptor.
4. The body still thinks it is hungry and continues feeding.
5. Leptin levels rise further.
6. Steps 4 and 5 continue until "enough" leptin gets through the block to turn off the hunger signal.
7. By this time, supernormal leptin levels *may be disrupting insulin function* in other body tissues.

So, I would say to the prophets of Insulin Resistance: watch the clock. Your 15 minutes of fame are almost up. Insulin resistance is an effect, not a cause, of obesity. Leptin tolerance is the key. And even that is not genetically programmed, but a MATTER OF CHOICE.

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