December 01, 1996
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 interaction with a
receptor in the brain's hypothalamus and other tissues, HHMI
scientists at The Rockefeller University reported in the February
15 issue of
"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," said
Jeffrey M. Friedman
, a Hughes
investigator at Rockefeller. "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 and at lower levels
in other tissues."
“Leptin may modulate the activity of other peptides and neurotransmitters that are known to affect feeding behavior in the hypothalamus.”
Jeffrey M. Friedman
Friedman and his colleagues have found Ob-Rb is mutant in
spontaneously diabetic (
) mice, which are consequently
massively obese and resist leptin treatment. 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 said.
The scientists identified the Ob-R receptors by
scanning for genes in the region of the
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 the
Ob-R gene can result in many different forms of the receptor.
"Leptin may modulate the activity of 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 co-authors include Gwo-Hwa Lee, Ph.D., Ricardo
Proenca, J. M. Montez, Kristine M. Carroll, Jerald G.
Darvishzadeh, and Jung I. Lee. Gwo-Hwa Lee, Ricardo Proenca
and Jung I. Lee also have HHMI appointments.