It has qualities so remarkable, it could come from the land of Oz (and could become the television doctor's next big thing, too): a compound derived from a tree growing in South and Central America prompted obese mice to lose 20 percent to 30 percent of their weight. It also allowed normal, healthy mice to chow down on fatty foods — as much as they wanted — and never become obese, accumulate excess fat or develop diabetes.
Oh, and it only worked in females.
A new study details the effectiveness with which a synthetic compound that mimics a flavenoid found in the leaves of the primula tree prompted the muscles of female mice to behave as if they were getting regular, intensive exercise.
Compared to female mice who got a placebo, those who got an oral formulation of a compound called 7,8-dihydroxyflavone (7,8-DHF for short) burned more calories, became more sensitive to the effects of insulin and developed body compositions that had more lean tissue and less fat.
The study also offers cruel justice to any woman who has struggled with weight loss while watching a man drop pounds effortlessly: Male mice who got 7,8-DHF saw no benefits from the compound. If they ate too much, they got fat. And once fat, 7,8-DHF did nothing to help them lose their excess weight.
In a strange twist, the experimental drug that produced these remarkable effects in female mice is on its way into human testing — as a treatment to delay or reverse the degenerative process of Alzheimer's disease.
Set to be conducted in China and Australia, the impending trials of the compound's safety and effectiveness may set the stage for its availability one day as a drug for weight loss or obesity prevention.
In the meantime, the lead author of the new research said he and his colleagues will seek to make a natural extract of 7,8-DHF available as a dietary supplement — a process that will require much less proof of the product's safety and effectiveness, but hasten its path to market.
The new research, published Thursday in the Cell Press journal Chemistry & Biology, demonstrates that 7,8-DHF stimulates the muscles to produce a hormone call brain-derived neurotrophic factor, or BDNF.
When produced inside the brain, the hormone BDNF appears to have powerful effects. It seems to protect the brain from a wide range of injuries, including trauma and oxygen deprivation. Researchers — including the authors of the latest research — are exploring its properties to find treatments for such devastating brain conditions as Huntington's, Parkinson's and Alzheimer's diseases, as well as for such conditions as depression.
Its name notwithstanding, BDNF is also secreted by the muscles, where its effect is no less dramatic. In female mice, BDNF activates a cascade of chemical effects that revved up calorie-burning and fostered normal, healthy weight without suppressing big appetites.
"We are quite excited about it," said senior author Dr. Keqiang Ye of the Emory University School of Medicine in Atlanta.
"An equivalent diet pill in humans would allow people to maintain a healthy weight, despite a high-fat diet," Ye added. "The pill would burn calories without affecting appetite."
Ye said the natural compound that inspired the synthesis of 7,8-DHF has a long history of safe consumption by humans and chimpanzees. In its raw form, however, the flavenoid has two problems, he said. It's not readily bioavailable — its chemical structure is either broken down or altered as it passes through the digestive system. And it's not concentrated enough to produce dramatic weight-loss or obesity-protection effects.
Those obstacles have impeded efforts to test and eventually use BDNF as a treatment for brain diseases. Forced to bypass the gut to administer the drug, researchers had to infuse the hormone directly into animals' brains to test its effects. While that can be done with a rodent, it's not a practical therapy for a human.
Ye and his colleagues set out to find a form of BDNF that is pure, powerful and practical enough to test as a drug for Alzheimer's disease. They screened thousands of experimental compounds for one that got around those shortcomings. The result — 7,8-DNF — provides a much more concentrated dose of the flavenoid than could be had by consuming its leaves. And it traverses the intestine intact.
Ye said a natural extract from the leaves of the primula tree (or from a plant called Godmania aesculifolia) could provide a sufficiently concentrated dose of 7,8-DNF to have a weight-loss effect, although he said it might be costly. At the same time, he acknowledged that a synthetic version of the 7,8-DNF is far more likely than a dietary supplement to have the dramatic effects shown in the new study.
Producing a drug to prevent and treat obesity, said "is a huge market, of course." But treating Alzheimer's disease seems more urgent. "After all," he said, "for obesity, there is diet and exercise. Once you've lost your memory, it's gone."
"Of course," Ye added, he and his colleagues would like to develop a drug that both cures Alzheimer's and treats obesity. "But we can only do one by one … It depends on the capital."
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