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Several strains of laboratory mice are homozygous for single-gene mutations that causes them to become grossly obese.These fall into two classes:
When ob/ob mice are treated with injections of leptin they lose their excess fat and return to normal body weight.
Study of these animals has led to an understanding of the action of leptin in humans.
Human leptin is a protein of 167 amino acids. It is manufactured in the adipocytes (fat cells) of white 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:
The absence of a functional hormone (or its receptor) leads to uncontrolled food intake and resulting obesity.
|Leptin also acts on hypothalamic neurons responsible for
In addition to its effect on the hypothalamus, leptin acts directly on
Mutations in the gene for leptin, or in its receptor, are rarely found in obese people.The rare cases:
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 human leptin in a 9-year-old girl who is homozygous for a frameshift mutation in her leptin genes. The findings:
The results of trials of recombinant leptin in obese humans who do not have mutations in both their leptin genes have not shown any great benefit in weight reduction.
Fat cells in mice also secrete a small protein (108 amino acids) called resistin.
Resistin causes tissues — especially the liver — to be less sensitive to the action of insulin, which is the hallmark of Type 2 diabetes. Blood glucose levels rise because of increased glycogenolysis and gluconeogenesis in the liver.
In humans, resistin is primarily a product of macrophages, not fat cells. Nevertheless, there is a strong association in humans between elevated levels of resistin, obesity, and Type 2 diabetes (over 80% of the people with Type 2 diabetes are obese).
This protein (of ~180 amino acids) is responsible for the transport of retinol (vitamin A) in the blood.When it is secreted in elevated amounts by fat cells, it
These actions counteract those of insulin. Elevated levels of RBP4 occur in humans with Type 2 diabetes mellitus (NIDDM).