Tubby Candidate Gene

In the 1970s, the tubby gene (normal: tub; mutated: tub) caused severe obesity in mice. Several other animal species, including humans, were subsequently found to have the tubby gene. This gene is one of several genes which, when mutated, lead to severe obesity. It provides an avenue for research into the genetic causes of obesity, and therefore potential therapies and cures.

Mice are excellent animal models for numerous diseases, disorders, and genetic characterizations. One reason for this utility is that mice can be raised in inbred colonies such that every mouse is of identical genetic background. Researchers can then manipulate one gene at a time and exercise selective breeding [Page 758]to create colonies with some mice that differ at only one particular gene. Sometimes, spontaneous mutations arise in a colony. Scientists can then use genetic analysis techniques to determine which gene spontaneously mutated, and the result of the mutation. At the Jackson Laboratory, a leading mouse supplier, two such spontaneous mutations arose, and the mice harboring the mutations developed severe obesity. One gene was named fat and the other tubby.

Fat and tubby mutants result in slow-onset severe obesity that does not ultimately progress to diabetes. Nevertheless, fat and tubby mice show hyperinsulinemia, hyperactivity of beta cells (in the islets of Langerhans of the pancreas), and degranulation of the beta cells.

In a study published in 1990 in the Journal of Heredity, scientists at the Jackson Laboratory determined that the inheritance of the tub mutation was autosomal recessive, that is, the gene is not on a sex chromosome but rather on an autosome, and a mouse must have both copies of its genes mutated to develop the severe obesity. A mouse with one tub gene and one normal gene would pass the tub gene to one-half of its offspring; these offspring, like the original mouse, would be carriers, showing no symptoms of obesity.

Tubby mice have a slow progression to obesity. The obesity becomes apparent within a few months of age. A mouse a few months of age is considered an adolescent. In addition, males become obese more rapidly than females. Similarly, males have a quicker progression of plasma insulin concentration and declining morphology of the pancreas.

Tubby mice are not sterile; however, they are relatively infertile in that they can produce offspring only if mated before the onset of severe obesity. Tubby mice have even fat distribution over the whole body. There are no regions with more pronounced fat deposits.

The tubby gene is located on the seventh murine autosomal chromosome. Researchers point out that although the gene for insulin II is also present on chromosome 7, the tub mutation does not have an effect on insulin structure or ratio of insulin I to insulin II levels.

In 1996, an article was published in the journal Cell outlining the molecular basis of the tub mutation. The scientists sequenced the normal gene and the mutant gene. They found that the normal gene is predominantly expressed in the brain, specifically in the hypothalamus. The hypothalamus is a region of the brain that, among other tasks, monitors body weight. It does so by regulating energy expenditure, and also has some control over appetite. Additionally, the scientists discovered that the normal mouse tub gene is 89 percent identical to a human gene, now also named tub. When the gene is read into a protein, the amino acid sequences of the two proteins (mouse and human) are 94 percent identical, with near-exact identity in the latter portion of the protein. These scientists also showed that the protein is hydrophilic (water soluble), and most likely not a cellular transmembrane protein.

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