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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:

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: This inhibition is long-term, in contrast to

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
  • the conversion of white adipose tissue (WAT) into "beige" adipose tissue. "Beige" cells metabolize food into heat rather than storing it as fat [Link]. In mice, at least, leptin promotes weight loss even with normal food intake.
  • the secretion of gonadotropin-releasing hormone (GnRH). Women who are very thin from limited food intake or intense physical training may cease to menstruate because of their lack of leptin-secreting fat cells. Treating them with recombinant human leptin can sometimes restore normal menstruation.
  • stimulating the sympathetic nervous system to modulate the balance between the formation and breakdown of bone.

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, but trials to see if it can reduce obesity in humans as it does in ob/ob mice have been disappointing.

However, the 16 September 1999 issue of The New England Journal of Medicine reported 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:

But 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.


Lipodystrophy is the term given for a condition (very rare) in which the person cannot manufacture adipose tissue. With no fat cells, these people do not make leptin, but of course cannot become obese as a result. They do, however, suffer some problems — most often Non Insulin-Dependent Diabetes Mellitus (NIDDM) ("Type 2" diabetes). Treatment with recombinant leptin helps them.


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).

Retinol Binding Protein 4 (RBP4)

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).

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27 March 2015