Controlling one's appetite, and waistline, depends less on will powerthan on won't power.
A protein in adipose tissue, leptin by name, generates that negative"stop-eating" signal to warn a person against consuming more foodthan is good for him or her. Paradoxically, many obese individualsproduce plenty of leptin, but somehow miss its message.
So do very corpulent mice, of a strain named db/db. That labelsignifies that the extremely overweight rodents in question haveinherited a double dose of the db obesity gene, which results indiabetes.
These over-eating mice are laboratory stand-ins for studying type IIdiabetes in humans. Unlike type I diabetics, who are unable to makeinsulin, type IIs produce plenty of the hormone, but target tissues failto respond to it, for reasons unknown. Doses of exogenous insulinhelp some patients overcome this defect.
Likewise, db/db mice make lots of leptin, but fail to tune in itsreminder to stop pigging out.
A scant six weeks ago, Millennium Pharmaceuticals Inc., inCambridge, Mass., reported cloning and characterizing the humanand mouse genes that encode a receptor in the brain, which bindsleptin, and broadcasts its message. (See BioWorld Today, Dec. 29,1995, p. 1.)
At the time, Louis Tartaglia, who heads Millennium's obesity drugprogram, told BioWorld Today, "The molecules that mediate thesignal off of the leptin receptor could be pharmaceutical targets fororally available drugs." His next goal, Tartaglia added, wasdetermining whether or not his leptin receptor gene is actuallyencoded by the mouse db gene.
A report in the Feb. 9, 1996, Cell found: "Evidence that the diabetesgene encodes the leptin receptor: identification of a mutation in theleptin receptor gene in db/db mice."
This fast-lane discovery means two things to Millennium, oneimmediate, the other prospective. "The finding," the company said,"qualifies as a milestone in Millennium's research collaboration withHoffmann-La Roche Inc. in obesity and type II diabetes, and triggersa corresponding milestone payment."
Farther along, Tartaglia and his associates expect, "it will lead to apill that will stimulate the receptor cascade directly, for treatingobesity, or the reverse _ inhibit leptin-receptor binding, as therapyfor cancer cachexia [tissue wasting] or anorexia."
Commenting on this latest Cell paper, Tartaglia said: "The mutationwe now report demonstrates that the receptor we cloned previously isessential for the leptin message to be sent. When it's mutated, leptincan do nothing." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.