Leptin: the Fat Hormone

Several strains of laboratory mice are homozygous for single-gene mutations that causes them to become grossly obese.

These fall into two classes:

ob/ob = mutations in the gene for the protein hormone leptin
When ob/ob mice are treated with injections of leptin they lose their excess fat and return to normal body weight.
db/db = mutations in the gene that encodes the receptor for leptin

Leptin is manufactured in fat cells (adipose tissue), and the level of circulating leptin is directly proportional to the total amount of fat in the body.

Leptin acts on receptors in the hypothalamus of the brain where it:

inhibits food intake
counteracts the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus).

Thus leptin provides homeostatic control of food intake and storage.

The absence of a functional hormone (or its receptor) leads to uncontrolled food intake and resulting obesity.

What about humans?

Humans fat cells also manufacture a leptin (a protein of 167 amino acids). However, mutations in the gene for leptin, or in its receptor, are rarely found in obese people.

The rare cases:

Extreme obesity in five members of two families that are homozygous for mutations (frameshift in one family, missense in the other) in their leptin gene; i.e., they are like ob/ob mice.
Extreme obesity among three members of a family that are homozygous for mutations in their leptin receptor gene; i.e., they are like db/db mice.

Recombinant human leptin is now available, and trials are underway to see if it can reduce obesity in humans as it does in ob/ob mice.

The 16 September 1999 issue of The New England Journal of Medicine reports the results of a year-long trial of recombinant leptin in a 9-year-old girl who is homozygous for a frameshift mutation in her leptin genes. The findings:

She began the trial weighing 208 pounds (94.4 kg), of which 123 lbs (55.9 kg) was fat (adipose tissue).
She was given daily injections of recombinant leptin for one year.
At the end of that time,
she had lost 36 lbs (16.4 kg), most of it fat.
Her appetite and thus food intake had decreased.
Her immune system made antileptin antibodies but these did not seem to interfere with the action of the hormone.

The results of trials of recombinant leptin in obese humans that do not have mutations in either their leptin gene or the gene for its receptor have so far not shown any great benefit in weight reduction.

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4 November 1999