Leptin, the appetite-suppressing drug that flunked tests for weight loss in people, is resurrecting hope with a study showing it worked better in mice when combined with other medicines.

The research showed obese mice lost weight when given a combination of leptin and either a generic liver drug or a second medicine used for enzyme deficiencies. Amylin Pharmaceuticals Inc. of San Diego, which acquired rights to leptin in 2006, wasn’t involved in the study, performed at Harvard University and the University of Michigan.

Leptin, a hormone, generated hope 10 years ago that it would be an effective treatment for obesity, and never delivered benefits because many people develop a resistance to the hormone in the brain. Today’s findings in the journal Cell Metabolism show a way researchers may be able to overcome that resistance, allowing obese people to control appetite and lose weight, the researchers said.

“We believe that we’ve identified the core mechanism that causes leptin resistance,” said the study’s senior author, Umut Ozcan, an endocrinologist at the Harvard-affiliated Children’s Hospital Boston, in a telephone interview on Dec. 30. “If this works in humans, it may create a new treatment plan for obese humans. Currently we don’t know whether it will be effective in humans or not."

Stroke Risk

About two-thirds of U.S. adults are overweight or obese, and obesity is the No. 2 cause of preventable premature death in the nation, behind smoking. Obesity raises the risk of heart disease, diabetes, cancer, high blood pressure, stroke and osteoarthritis, according to the Centers for Disease Control and Prevention, based in Atlanta.

Researchers first demonstrated in the study that the brain cells of obese mice have increased stress in an area called the endoplasmic reticulum, which assembles and dispatches proteins for the body. In obese people, this area doesn’t function properly, and eventually that works to block leptin action in the brain.

They also showed that two drugs reduced the stress and resensitized this cell area: tauroursodeoxycholic acid (TUDCA), a substance found in the bile of black bears and used in generic drugs to treat liver disease, and Medicis Pharmaceutical Corp.’s Buphenyl, used to treat enzyme deficiencies linked to high levels of urea.

Drug Combination

Obese mice that were given either TUDCA or Buphenyl for 10 days, followed by leptin, were more likely to lose weight than mice treated with only leptin, Ozcan said. With 15 days of leptin treatment plus either TUDCA or Buphenyl, the mice showed a “highly significant reduction in the body weight when compared to the control mice which were only treated with leptin,”he said.

The researchers found high doses of TUDCA and Buphenyl were necessary to reduce stress on the cell’s key area. Ozcan said future studies should look at what dose would work in humans. Other studies are needed to identify why reducing stress on the cell’s endoplasmic reticulum blocks leptin resistance, he said. More-potent medicines are needed to help reduce this cellular stress so lower doses of the medicines can be used.

Leptin, discovered in 1994, is a natural hormone made by fat cells. When more fat is stored in the body, leptin rises, signaling to the brain that the body has had enough to eat. Earlier studies of leptin found binge-eating mice that lacked leptin lost weight when given the hormone. When obese people took leptin, researchers found the patients didn’t benefit, because they already had elevated levels of the hormone.

Other Studies

Amylin acquired the rights to leptin for an undisclosed amount in 2006 from Amgen Inc. of Thousand Oaks, California,, which had paid $20 million in 1995 for rights to the hormone. Amylin has pursued a different line of research on leptin and is in the second of three phases of human testing of the hormone in combination with another drug, pramlintide, the active ingredient in its diabetes drug Symlin.

The trial of about 600 patients is expected to be completed in mid-2009, said Alice Izzo, a spokeswoman for Amylin. The company declined to comment on the study in Cell Metabolism. An earlier phase-two study found that the combination of pramlintide and leptin reduced body weight by an average of 12.7 percent, she said.

The research released today was funded by faculty grants from Children’s Hospital Boston, a teaching venue for Harvard Medical School.