A molecule in tree leaves slows weight gain in female, but not male, mice on a high-fat diet. Scientists say there’s a chance it could work for people, too.
The molecule, 8-dihydroxyflavone (7,8-DHF), appears to work by mimicking the effects of a growth factor induced by exercise. In the mice, the molecule could increase energy expenditure by acting on muscle cells without suppressing appetite.
“An equivalent diet pill in humans would allow people to maintain a healthy weight, despite a high-fat diet,” says Keqiang Ye, professor of pathology and laboratory medicine at Emory University School of Medicine. “The pill would burn calories without affecting appetite.”
Published in the journal Chemistry & Biology, the findings highlight the need to study both sexes while developing drugs for obesity and related conditions and also reveal a surprising effect of a molecule previously thought to act mainly on brain cells, instead of muscle cells.
Researchers have been studying brain-derived neurotrophic factor (BDNF) and its receptor TrkB. Previous research has shown that BDNF is secreted after physical exercise. Lack of BDNF is also thought to play a role in neurodegenerative diseases such as Alzheimer’s disease. However, BDNF degrades quickly in the body.
Ye and his colleagues discovered 7,8-DHF while looking for ways to activate TrkB with drugs in the absence of BDNF.
The molecule is found in Godmania aesculifolia and primula tree leaves from Central and South America. A 7,8-DHF pro-drug (meaning that it is hydrolyzed in the body to 7,8-DHF) is planned for phase I human clinical trials in Shanghai and Australia, Ye says.
Why not males?
When mice were fed 7,8-DHF along with a high-fat diet, females maintained their appetites but kept a healthy weight and metabolic profile; males, on the other hand, still developed obesity and diabetes. The mechanisms behind this sex difference are unknown, but interactions between BDNF/TrkB signals and estrogen might play a role, Ye says.
“This drug has been tested in a variety of neurological diseases and exhibits promising efficacy in both male and female animal models,” Ye says. “Further investigation is necessary to explore why it selectively burns fat in the female mice.”
Another surprise was that 7,8-DHF appears to act on muscle cells and does not suppress appetite. BDNF is thought to act on the hypothalamus, part of the brain that controls appetite. In muscle cells, 7,8-DHF appears to activate production of an mitochondrial uncoupling protein called UCP1, which was first discovered in brown fat and helps generate heat.
Chi Bun Chan, now assistant professor of physiology at University of Oklahoma College of Medicine, is the study’s first author.
The National Institute of Diabetes and Digestive Kidney Diseases, the National Institute of Deafness and Other Communication Disorders, and the Oklahoma Center for the Advancement of Science & Technology funded the work.
Source: Emory University