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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
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," 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 (db) 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 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 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.
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