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Even with a lower food intake, many dieters just can't seem to lose weight — perhaps because their bodies aren't burning it off. Yi Zhang, a biochemist at the University of North Carolina at Chapel Hill, and his colleagues have discovered that loss of a specific enzyme causes obesity in mice by snuffing out the body's ability to burn energy but leaving appetite unaffected. On page 757, the authors show that the enzyme, Jhdm2a, helps to control the expression of metabolic genes. Loss of the enzyme's function causes a metabolic defect that makes mice accumulate fat. Zhang tells Nature about finding a new pathway involved in obesity.

How did you discover this enzyme's function in metabolism?

We study the role that the modification of histone proteins has in the regulation of gene expression. Histones are a class of proteins required to organize DNA into chromosomes, and Jhdm2a is an enzyme that modifies histones by removing methyl groups from specific locations. By testing mice in which the Jhdm2a gene had been knocked out, we had previously learned that the Jhdm2a protein is required for sperm maturation. To our surprise, when these knockout mice got older, they grew much fatter than their littermates. We began to notice this when they were about three months old, and by six months old they were significantly obese.

How did you connect the obese animals' condition to defects in metabolism?

First, we checked whether the knockout mice eat more than their littermates, and found that they don't. So then we turned to thinking about energy expenditure — we figured that the obese mice must be expending less energy. We found that the expression of certain metabolic genes was defective in these mice, leading to lowered fat-burning.

Was reduced energy expenditure the only result of the enzyme's absence?

No, the mice also exhibited defective heat generation, or thermogenesis. Normally, mammals have a mechanism for maintaining body temperature in a cold environment. But Jhdm2a-knockout mice cannot maintain their body temperature in the cold.

What do your results mean for human dieters?

Some people say that even if they just drink water they gain weight. There might be a good reason; maybe such people have a low basal metabolic rate because they have a defect in this gene, or in genes performing a similar function. An agonist that can enhance the function of this protein could potentially be useful in increasing basal metabolism.