Hormone Linked to Stored Fat Could Explain Atkins Diet

BOSTON, June 6 -- In a discovery that may explain the successes of the Atkins diet, investigators have found that a single hormone may switch on the use of stored fat for fuel when all else fails.

The hormone, fibroblast growth factor 21 (FGF21), is expressed in the liver and drives the production of so-called ketone bodies, which in some circumstances provide up to 70% of the energy required by the brain, according to two studies reported in the June issue of Cell Metabolism.

The findings may explain the fat-burning benefits sometimes seen in high-fat, low-carbohydrate diets, such as the Atkins diet, said Eleftheria Maratos-Flier, M.D., of Beth Israel Deaconess Medical Center here.

And the discovery may lead to new approaches to obesity, Dr. Maratos-Flier said. "We think these findings would increase the desirability of a drug that (might work through this mechanism) to increase fat oxidation in the liver," she said.

Dr. Maratos-Flier and colleagues reported that in order for mice on a carbohydrate-restricted diet -- or simply kept without food -- to switch gears and begin burning fat, they need increased blood levels of FGF21.

The accompanying study, led by Steven Kliewer, Ph.D., of the University of Texas Southwestern Medical Center in Dallas, also found that the hormone breaks down fat -- both in animals forced to fast, as well as those with chronically elevated concentrations of FGF21.

The Dallas researchers also showed that as animals adapt to a food shortage, the hormone leads to energy-conserving behavioral changes. They move less and sleep more.

"It's startling that you can give one hormone and flip the whole metabolic profile," Dr. Kliewer said. What's more, he said, the hormone appears to counteract the effects of too much food.

"What's really exciting is that mice with excess FGF21 -- even when they are fed -- look like they are fasted," Dr. Kliewer said.

Feeding mice a high-fat, low-carbohydrate diet -- a ketogenic diet -- leads to the breakdown of fatty tissue and weight loss, accompanied by the production of ketone bodies, which are used by tissues as replacement energy sources, Dr. Maratos-Flier and colleagues said.

But the details of the process were not completely understood, so they performed a genetic scan on mice fed such a diet for 30 days, looking for changes in gene activity.

"We saw a dramatic increase in FGF21 in the livers of the mice," she said. "We thought, 'Maybe there is something to this.'"

In a series of experiments, she and colleagues showed that fasting mice and those fed a ketogenic diet both developed high levels of the hormone in the liver and in the blood.

Feeding the mice a normal diet resulted in a rapid decline of the hormone levels.

Moreover, they found, feeding the ketogenic diet to mice genetically engineered to lack the hormone led to a fatty liver, high blood lipids, and reduced levels of ketone bodies.

The Dallas group showed that FGF21 is induced by peroxisome proliferator-activated receptor alpha (PPAR-alpha), which is known to be involved in the regulation of fat metabolism during starvation.

PPAR-alpha is also the target of the fibrate drugs used to treat high cholesterol and triglycerides.

"When you step back, the whole thing makes sense," Dr. Kliewer said. "During fasting, the liver hormone communicates with adipose tissue to send fat to the liver. It turns on the metabolism of fat into ketone bodies -- and at the same time, it sensitizes the animals to going into torpor to conserve energy."

"It's clear that FGF21 is a principal component of the fasting or starvation response," he added.

Dr. Kliewer said there's an "obvious possibility" that the hormone is responsible for the benefits seen by some people when they follow the high-fat, low-carbohydrate Atkins diet.

But Dr. Maratos-Flier cautioned that it's still not clear that the effect of such a diet in humans is the same as that seen in mice.

For instance, she said, "it may be that some people are more likely to turn on FGF21 than others." To find out, she now plans to study FGF21 levels in people.

The work by the Dallas group was supported by the National Institutes of Health, the Robert A. Welch Foundation, the Betty Van Andel Foundation, the Smith Family Foundation Pinnacle Program Project Award from the American Diabetes Association, and the Howard Hughes Medical Institute.