In Spite of Failed History, Leptin May Help Fight Fat

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Leptin is an appetite-suppressing hormone that occurs naturally in humans. When an individual is eating fat cells produce a chemical which should turn on the production of leptin and send a signal to the hunger center of the brain that says “stop eating.” After its discovery in the mid-1990s, it was thought to be the answer to fighting obesity. Tested in obese mice it was found that mice that lacked leptin lost weight when treated with the hormone. When used in obese humans the same weight loss occurred but the success was only temporary. Obese mice and people seemed to lose the hunger control sequence that was necessary for them to stop eating.
A study lead by Dr. Umut Ozcan, of Children’s Hospital Boston and Harvard Medical School, has discovered that with the addition of two drugs already approved for use in humans the brain can be made to respond to leptin and may lead to more permanent weight loss. The research team said that when leptin lost its power in fat mice, and they were then treated with one of the two drugs they overcame leptin resistance. This raises the possibility that the early hopes for leptin in the treatment of obesity could be realized.
The team found that brain cells in obese mice have increased stress in the endoplasmic reticulum or ER, a structure within cells where proteins are assembled. Within the obese body the structure is "overwhelmed" and begins blocking incoming chemical signals. After finding the stress-blocked leptin response, the team searched for ways to re-activate the brains response to leptin by reducing the ER stress. Two known drugs act as stress reducers, 4-phenyl butyric acid or PBA, which is used to treat cystic fibrosis, and tauroursodeoxycholic acid or TUDCA, used to treat a liver disease; both were used in the study.
One of two drugs was given to mice on a high-fat diet, and then the mice were injected with leptin. According to Ozcan there was a significant weight loss in the mice. “Reduction of ER stress makes the mice sensitive to the leptin, which is bringing new hope for the treatment of obesity,” he said.
The drugs are classified as “chemical chaperones” and help leptin gain entry into the brains of mice and reduce the hunger signals that kept them eating. The drugs are safe for humans, but there is no guarantee that they would have the same effect in people as in mice.
Drugs previously marketed to fight obesity have had only limited success and sometimes have severe side effects. With more than 1.8 billion people overweight or obese in 2007 medical treatments to help relieve the problem could save lives and save hundreds of thousands of dollars in medical costs by reducing the medical problems related to obesity