Mutations in a Leptin Receptor Cause Obesity in Mice

The weight-reducing effects of leptin, a hormone that signals the size of the body’s fat stores, result from an interaction with a receptor in the brain’s hypothalamus, report scientists from the Howard Hughes Medical Institute (HHMI) at The Rockefeller University in the Feb. 15 Nature.

“When we found leptin in 1995, we suspected it acted in the hypothalamus, a region of the brain known to regulate food intake and body weight,” says Jeffrey Friedman, M.D., Ph.D., professor and associate investigator. “In our current work, we have determined that there are at least six different forms of the leptin receptor, known as Ob-R. One of these forms, Ob-Rb, is expressed at a high level in the hypothalamus.”

Friedman and his colleagues have found Ob-Rb is mutant in diabetic (db ) mice, which are consequently massively obese and resist leptin.

While Ob-Rb appears to be critical for the weight-reducing effects of leptin, the functions of other forms of Ob-R are not known, Friedman says. Another form, Ob-Re, is produced in fat tissue and encodes a secreted form of the receptor, which may be a carrier protein for leptin. A choroid plexus form of the receptor, Ob-Ra, initially identified by investigators at Millennium Pharmaceuticals and Hoffmann-La Roche, may transport leptin into the brain. More research is required to define the functions of the other forms of the leptin receptor.

In 1995, the Millennium group led by Louis Tartaglia, Ph.D., cloned a leptin receptor, Ob-R, from the brain’s choroid plexus. This brain structure makes the cerebrospinal fluid that bathes the brain and spinal column. They identified Ob-R by virtue of its ability to bind to leptin, the hormone made by the mouseobese gene, which Friedman and his colleagues isolated and cloned in 1994. The Millennium team also identified a second form of the receptor that is the human equivalent to Ob-Rb.

In the current work reported in Nature, Friedman and his team identified at least six different forms of the Ob-R protein and propose that many additional forms of this receptor exist. The scientists identified the Ob-R receptors by scanning for genes in the region of the db mutation on mouse chromosome 4. They found that one of the genes in this region was identical to the Ob-R gene. They observed, however, that Ob-R is alternately spliced, resulting in many different forms.

“Leptin may modulate the activity of neuropeptide Y, glucagon-like peptide 1 and other peptides and neurotransmitters that are known to affect feeding behavior in the hypothalamus,” Friedman explains. “Leptin also may affect other tissues that have Ob-Rb receptors, including fat.”

Friedman’s coauthors include Gwo-Hwa Lee, Ph.D., Ricardo Proenca, M.S., J. M. Montez, B.S., Kristine M. Carroll, B.S., Jerald G. Darvishzadeh, B.S. and Jung I. Lee, B.S. Gwo-Hwa Lee, Ricardo Proenca and Jung I. Lee also hold HHMI appointments. The National Institute of Diabetes and Digestive and Kidney Diseases supported the research.