OHSU Scientists Shed Light On The Role Of Leptin In Body Weight Regulation

November 28, 1997

Leptin, a hormone produced by fat cells, has been the subject of extensive research since its discovery in 1994 when it was implicated in the regulation of body weight and appetite. Now scientists at Oregon Health Sciences University have discovered evidence indicating that certain obese mice develop a tolerance for leptin. Their findings appear in the Nov. 28, 1997 issue of Science and shed light on the role of leptin.

"It has been known that high levels of leptin correlate with increased body fat in both humans and mice," explains Bruce Boston, M.D., lead author of the paper and assistant professor and scientist in the pediatrics department at OHSU. "Whereas low levels of leptin are associated with low body fat, extremely low levels of leptin are associated with starvation and compel an animal to eat voraciously when food becomes available."

Boston further explains that fat cells produce the protein leptin which enters the blood stream and travels to the brain where it binds with receptors on nerve cells in the hypothalamus of the brain. "The leptin pathway creates a feedback loop for body weight regulation," says Boston. High levels of leptin signal that enough food has been consumed, whereas very low levels initiate the starvation response.

Since low levels of leptin are thought to turn up an animal's appetite, it was hypothesized that increasing an animals leptin level would have the opposite effect and turn down the appetite. However, Jeffrey Friedman, Ph.D., of the Rockefeller University has recently demonstrated that several types of obese mice, including a strain called yellow agouti mice, do not lose weight when they are given increased levels of leptin. The obese agouti mice thus appeared resistant to the leptin hormone.

Friedman's work suggested that animals may become obese because they are unable to respond to leptin. This paper by Boston and senior author Roger Cone, Ph.D., of OHSU's Vollum Institute, argues for a very different conclusion. Their data implies that obese animals have already responded to the high leptin level in their system and simply cannot respond to any additional leptin. This raises questions about the potential therapeutic value of leptin for the treatment of obesity.

Boston further explains that decreasing the levels of leptin may have evolved to help the body respond to starvation, but high levels of leptin may not play an important role in preventing animals from becoming obese.

Further Details from Science's Press Digest

Leptin and obesity: Not long ago, researchers discovered that giving the hormone leptin to obese, leptin-deficient (lepob/lepob) mice caused dramatic weight loss. But leptin has little effect on normal mice or in other mouse models of obesity. Here, Boston et al. disprove one theory some scientists had posed to explain this leptin-resistance, which is a hall mark of obesity in so many species.

Obesity in the so-called lethal yellow (Ay/a) mouse is caused by a defect which interrupts the flow of brain signals that would otherwise curb the animals' eating. Specifically, there is a disruption in the signal from a region of the brain called the arcuate nucleus proopiomelanocortin (POMC). Administration of leptin to these mice has no impact on their eating behavior, leading researchers to speculate that their signaling defect acts as a direct block to leptin action. If true, this hypothesis would link the POMC and leptin pathways, and shed light on the mechanism by which leptin is used or resisted in the body. But the authors disproved this theory. They showed that leptin-deficient (lepob/lepob) mice which also carry the Ay/a mutation are fully sensitive to injections of leptin÷they lose weight. Thus, leptin resistance in the Ay/a mouse is more likely caused by classic desensitization÷because the animals have a normal response to leptin, they are desensitized to higher leptin levels.

Oregon Health & Science University

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