Like our earliest ancestors, we metabolize food to prepare for both feast and famine. The body stores energy as fat when food is plentiful and burns it later when food is scarce. But we're only starting to learn the details of how that transition occurs.

A key molecular switch appears to regulate the critical balance between fat storage and burning—a finding that could lead to treatments for obesity, cardiovascular disease, and diabetes. Ronald M. Evans, an HHMI investigator at The Salk Institute for Biological Studies in California, has identified this "fat switch" as PPARd, a nuclear receptor in the family known as peroxisome-proliferator-activated receptors. (Nuclear receptors are activated by hormonal fats—fat derivatives that regulate cellular function much as hormones do—which trigger them to turn on specific genes.) Two other PPARs were already known to play a role in fat metabolism. Indeed, drugs activating these two receptors are used to treat hyperlipidemia—a condition characterized by elevated levels of lipids, including cholesterol, in the bloodstream—and type 2 diabetes. But the function of PPARd remained a mystery, largely because no ligand had been found to activate it.

Evan's group got around this problem by creating transgenic mice with PPARd receptors that were permanently activated in fat cells. In the April 18, 2003, issue of Cell, his team describes its experiments and findings on PPARd over seven years. Remarkably, young mice with activated PPARd weighed 20 percent less than normal counterparts on the same diet, and by 1 year of age, they were 35 percent lighter. Moreover, the transgenic mice were protected against weight gain on a high-calorie, high-fat diet, while normal mice became obese. In addition, in 2001, Glaxo researchers discovered a chemical to activate PPARd. Evans's group gave the chemical to obese mice that ate all the time because of a defect in leptin, an appetite regulator, and the mice lost weight. "When you activate this fat switch, you increase fat burning," concludes Evans.

These results raise the possibility of a new approach to obesity treatment—"losing weight by controlling metabolism, rather than behavior," says Evans—which has pharmaceutical companies such as Lilly and GlaxoSmithKline eagerly searching for drugs to activate PPARd. "The exciting thing about nuclear receptors such as PPARs is that we know ligands for them can be drugs and there's never a problem with absorption in the body," notes Mitchell A. Lazar, director of the Penn Diabetes Center at the University of Pennsylvania School of Medicine.

Lazar, who also studies PPARs, nevertheless cautions that there are many remaining questions about PPARd. For example, does tilting the balance toward fat burning raise body temperature? Does PPARd, which is ubiquitous throughout the body, play different roles in different tissues? Would a ligand for PPARd activate the other PPARs as well?

As he pursues answers to these and related questions, Evans is optimistic about ultimate success—though with possible qualifications. "I am convinced that we can activate fat metabolism in people," he says. "The issue now is whether it will show a favorable safety profile over a long period of time."

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Photo: Misha Gravenor

Reprinted from the HHMI Bulletin,
September 2003, pages 10-19.
©2003 Howard Hughes Medical Institute