Endeavors magazine: The overweight enzyme

Weight-loss medications that curb appetite may leave you feeling fuller a few hours longer. But improving the body’s metabolism might be just as effective and even safer.

Yi Zhang, a biochemist in the School of Medicine, has discovered that the enzyme JHDM2A affects the expression of metabolic genes and the ability of muscle to burn energy. If defective, the enzyme can harm the body’s metabolism and lead to weight gain. Zhang says that the study is the first to link obesity in mice to a faulty metabolism that doesn’t affect appetite, a function of the nervous system.

“This particular mouse model affects only the metabolism and doesn’t affect brain function,” he says. “It could be valuable for testing antiobesity drugs for humans, since a drug that increases metabolism is better than a drug that suppresses appetite and affects the brain.”

In the study, which was published in the journal Nature in February, Zhang and colleagues knocked out the gene that produces JHDM2A in mice and found that both males and females became obese after six months. The mice became less effective at generating body heat. They also had insulin resistance and increased lipid levels — characteristics linked to human metabolic disorder.

Zhang and his colleagues investigated JHDM2A’s role in metabolism after testing the enzyme’s function in spermatogenesis, the process of sperm-cell development. Zhang originally impaired the mice’s JHDM2A enzymes to test for infertility and discovered that the enzyme is required for spermiogenesis, the final step in the development of a sperm cell. (See Endeavors, Spring 2008, “A suspect gene for faulty sperm.” ) A few months after having their JHDM2A enzymes knocked out, Zhang’s mice became noticeably obese.

Scientists will have to do more research to determine whether the mouse results would be similar in humans. But Zhang’s study offers a potential solution: enhance the gene’s function to increase the body’s basal metabolism (the number of calories you burn by sitting or being inactive all day). “It will be important to test whether the gene is relevant to human obesity,” he says. “If so, then an agonist, which promotes the function of the gene, can be an antiobesity drug.”

Deborah Neffa is a graduate student in the School of Journalism and Mass Communication at Carolina.

Yi Zhang is a professor in the Department of Biochemistry and Biophysics in the School of Medicine, and a Howard Hughes Medical Institute investigator.