Duke Study Suggests New Class Of Drugs Could Bypass Leptin Loop

April 29, 1996

DURHAM, N.C. -- Animal studies at Duke University Medical Center show that the protein
leptin's role in weight loss has as much to do with burning stored fat reserves as it does with
signaling the brain that the stomach is full -- a discovery that could lead to a new class of drugs that
bypass the leptin brain circuit and target the fat cell itself.

Duke researchers say their study, reported today in the journal Nature, is the first to
demonstrate how leptin initiates the burning of stored fat, a process that has been postulated but never proven. In fact, their study shows that leptin is only the first step in a series of events that ultimately boosts fat metabolism, according to study authors Sheila Collins and Richard Surwit.

Leptin was identified last year as a protein that regulates body weight via appetite
suppression. But the complex circuit by which leptin begins the weight loss cycle is defective in
some obese animals and likely in obese humans, researchers found -- a theory confirmed by studies
showing that obese humans have elevated leptin levels yet remain obese. Researchers around the
country theorize that leptin remains elevated because the fat cells never receive its "slimming"

In studying the leptin loop, Duke researchers discovered they could apply a hormone -- a
synthetic form of noradrenaline -- directly onto the surface of fat cells, essentially bypassing the
leptin circuit. Receptors on the fat cell's surface, called B3 adrenergic receptors, receive the hormone's signal and transmit it inside the cell. The signal initiates a chain of events that results in the burning of stored fat.

Specifically, mice on a high-fat diet that received the synthetic noradrenaline stayed as slim as mice on a low-fat diet that received no noradrenaline. Results of this study were reported April 19 in the Journal of Biological Chemistry.

"Our results suggest that a class of drugs called B3 adrenergic receptor agonists might help in
weight loss," said Collins, a Duke pharmacologist and co-author of the study. "These drugs could
bypass the leptin system altogether and work at the fat cell site itself. The B3-adrenergic agonist
would stimulate the receptor on fat cells and initiate the burning of stored fat."

Based on results of the first study, Collins and Surwit, professor and vice chairman of the department of psychiatry, began to search for the pathway by which leptin signals the body to burn fat. Using genetically obese mice that lacked the leptin protein, researchers administered leptin to one group and a saline placebo to the other group. Because the genetically obese mice produced no natural leptin, it was easier to track the effects of the artificial leptin.

Results of the study showed that leptin does, in fact, signal the sympathetic nervous system
to release noradrenaline onto brown fat, sometimes referred to as "good" fat. This step appears to be near the endpoint of the leptin "feedback" loop. The loop begins with white fat cells, or undesirable fat. As the body accumulates white fat, more and more leptin is secreted into the bloodstream, essentially signaling the body to slim down.

"Leptin appears to be a sensor of fat cell size, so that when the cell reaches a certain
proportion, it sends a signal that elicits some metabolic response to eliminate fat," Surwit said.

Leptin travels through the bloodstream to the brain, where it targets clusters of neurons in
the hypothalamus, a brain structure that regulates food intake and metabolism, among other
functions. When leptin binds with receptors on these neurons, it sends a signal to the body to
decrease food intake. In addition, the Duke team showed that leptin also stimulates the sympathetic
nervous system to release noradrenaline onto the surface of brown fat cells.

Noradrenaline binds with B3 adrenergic receptors on the fat cell surface. This binding
transmits a message inside the cell, telling it to burn calories and release heat energy. As the
process continues, energy burned by brown fat exerts its metabolic effects on white fat -- in essence
"burning" stored white fat.

In demonstrating noradrenaline's fat-burning role, Duke researchers have explained why
leptin causes genetically obese mice to lose more weight than can be accounted for by appetite
suppression alone. They showed that leptin delivers a second signal to the brain: one that triggers
the release of noradrenaline onto the fat cell.

Currently, Collins and Surwit are investigating how defects in the feedback loop may be
involved in diet-induced obesity. The Nature study reported today was co-authored by professor
Cynthia Kuhn of Duke University and Andrew Swick and Boris Chrunyk of Pfizer Central

Duke University

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