This information should help speed the development of more natural and safe weight-reducing drugs to treat chronic obesity.
Researchers anticipate that leptin will have fewer side effects than current controversial weight-loss drugs such as Redux (dexfenfluramine) or fen/phen (fenfluramine and phentermine).
Since the discovery in 1994 of the obesity gene and its product, the fat-busting protein leptin, scientists have been racing to understand and apply this modern marvel. The ob gene -- ob for obesity -- was moved into mice in 1995, and the photo of the fat mouse next to the thin mouse with the ob gene was carried by nearly every media outlet in the nation.
Overnight the ob gene became the world's first celebrity gene, frequently mentioned in popular publications such as Newsweek, Time and The Wall Street Journal.
All of the reports and research on the ob gene and leptin thus far have assumed that the protein acts by causing a hormonal response in the brain, causing the body to feel satiated. Kim, of Purdue's Department of Biochemistry, has discovered that these findings are only partly correct. He was able to show that production in fat cells also was slowed by leptin.
The finding gives scientists the first indication that leptin suppresses biochemical reactions in fat cells without the participation of the brain.
In recent years physicians have taken a different attitude toward using pharmaceutical products to treat obesity. This isn't just some cosmetic desire for thinner thighs in 30 days.
According to a recent editorial in the New England Journal of Medicine, obesity affects 58 million people in the United States, contributing to 300,000 deaths each year by adding to the risk of heart attacks, strokes, diabetes and some cancers.
Physicians have begun to regard obesity as a chronic disease, not a behavioral problem, a change that the editorial described as a "paradigm shift." This change in medical thinking has fueled the race to discover a safe pharmaceutical product that treats obesity.
When researchers injected laboratory mice with leptin, previously obese mice became as thin as rodent track stars. "It's true that the animal isn't eating as much when it is given leptin," Kim says. "But that doesn't mean that the brain is initiating this. Whenever we eat, we alter the hormonal status of the body. The body has to tell its various parts to do something with this food that has been ingested. When leptin inhibits fat synthesis, it causes the body to have extra food in its system, which causes the hormonal system to send a message back to the brain saying that the body is satiated and to stop eating.
"So leptin's interaction in the brain isn't the whole story. Leptin also appears to act via pathways that are independent of the brain. My thinking is that it works by inhibiting the synthesis of fat in fat cells and increasing the burning of fat in muscle cells. It works at an enzymatic, cellular level."
Kim has found that the ob gene causes the muscle cells to produce leptin and suppresses a gene that produces an enzyme known as acetyl-CoA carboxylase, or ACC, which is essential for fat production.
Not only will this new information speed the process of delivering a pharmaceutical product to consumers, but it also should speed research on leptin, Kim says. "Research is much easier, and experimental results can be interpreted more clearly, if you can use cell cultures in petri dishes instead of whole animals in your studies," he points out.
The research was supported by grants from the National Institutes of Health and the Juvenile Diabetes Foundation, and was described in the June issue of The Journal of Biological Chemistry.
In addition to discoveries of leptin's role in cellular fat metabolism, Kim and his colleagues also have found a way to produce longer-lasting leptin.
"Native leptin produced in the body is short lived," he says. "Therefore, researchers have to give a dose to a mouse every day. Because people are larger, they would have to take it even more often than mice. If people have to inject themselves with leptin or take a pill every hour, this isn't going to be a practical method of treatment for obesity."
Although leptin is produced by the fat cells of mammals, researchers rely on recombinant bacteria to produce the compound. Purdue researchers have developed a method of altering this process so that it produces leptin that lasts twice as long as the naturally produced protein.
"We've been able to modify leptin so that it can survive longer in the system without losing its ability to inhibit fat synthesis," Kim says. "Our next step will be to modify this improved leptin so that it can be produced commercially in large quantities through biotechnology."
The researchers are in the process of filing for a patent on the new, long-lived form of leptin.
Source: Ki Han Kim, (765) 494-1666; e-mail, email@example.com
Writer: Steve Tally, (765) 494-9809; e-mail, firstname.lastname@example.org
Purdue News Service: (765) 494-2096; e-mail, email@example.com
NOTE TO JOURNALISTS: A black-and-white photo of Ki-Han Kim in his lab is available from the Purdue News Service, (765) 494-2096 or download here. The citation for the Journal of Biological Chemistry article mentioned in this release is Vol. 271, No. 24, June 14, 1996. The NEJM editorial mentioned in the story appeared in the Aug. 29, 1996, issue, Vol. 335, No. 9.
Obese Gene Expression Alters the Ability of 30A5 Preadipocytes to Respond to Lipogenic Hormones
Yinglin Bai, Shaoying Zhang, Kyung-Sup Kim, Jung-Kee Lee, and Ki-Han Kim, Department of Biochemistry, Purdue University, West Lafayette, Indiana
Leptin, the product of the ob gene, controls food-intake and weight loss in the ob mouse. Although the target(s) of the circulating leptin is presumed to be the brain which then orchestrates food-intake and weight loss, how leptin functions in the process of weight loss is unknown. In this report, we present evidence that ob gene expression in cultured cells suppresses acetyl-CoA carboxylase gene expression and lipid synthesis which are induced by hormone treatment. This is the first example in which leptin has been found to suppress defined biochemical reactions that contribute to lipid accumulation without the participation of the brain.
Purdue biochemistry Professor Ki-Han Kim pipettes a cell culture onto a petri dish in his laboratory. Kim has found that the protein produced by the human obesity gene has an effect on fat cells in the body. Researchers had previously thought that the protein, leptin, worked only by promoting changes in the brain. (Purdue Agricultural Communications photo by Michael Gibson)
Black-and-white photo, electronic transmission, and Web and ftp download available. Photo ID: Kim/Leptin.
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