Low-carb diets' effects linked to increased levels of FGF21

Metabolism
Low-carb diets' effects linked to increased levels of FGF21
By Cell Press, Jun 6, 2007 - 4:00:37 PM

The benefits sometimes seen in those on a low-carbohydrate, high-fat diet may depend on increased levels of a newly identified starvation hormone produced by the liver, according to a report in the June issue of the journal Cell Metabolism, published by Cell Press. Two studies in the issue show that the hormone plays a critical role in the metabolic shift seen in animals after a period of fasting and in those fed an Atkins-like diet. That shift is characterized by an increased reliance on fat stores as an alternative source of fuel when glucose, the body?s primary energy source, plummets.

A team led by Eleftheria Maratos-Flier of Harvard University reports evidence that increased blood levels of liver-derived fibroblast growth factor 21 (FGF21) are required for fasted mice and mice on a carbohydrate-restricted diet to switch gears and begin burning fat. Likewise, an accompanying study led by Steven Kliewer of the University of Texas Southwestern Medical Center found that FGF21 mobilizes fat in food-restricted animals and those with chronically elevated concentrations of the liver hormone. Kliewer?s team further showed that the hormone contributes to energy-conserving behavioral changes as animals ride out food shortages.

What?s really exciting is that mice with excess FGF21?even when they are fed?look like they are fasted, Kliewer said. It?s startling that you can give one hormone and flip the whole metabolic profile.

We think these findings would increase the desirability of a drug that [might work through this mechanism] to increase fat oxidation in the liver, added Maratos-Flier, noting that the rise in obesity has contributed to a growing epidemic of nonalcoholic fatty liver disease. Although the physiology remained uncertain, pharmacological studies of mice and diabetic monkeys had previously shown promise for FGF21 therapy as a means to lower blood sugar and lipids and stave off weight gain.

Mammals survive periods of nutrient deprivation by shifting from carbohydrates to so-called ketone bodies as a primary fuel source. Ketone bodies are produced from fatty acids transferred from storage in fat tissue to the liver when carbohydrates are scarce.During prolonged fasts, ketone bodies can provide nearly half of baseline energy requirements and up to 70% of the energy required by the brain.

Earlier studies also showed that feeding rodents a high-fat, low-carbohydrate (ketogenic) diet induces lipid oxidation associated with weight loss, according to Maratos-Flier. Yet the underlying mechanism responsible for the profound physiological changes that the diets induced wasn?t fully understood.

In the new study, Maratos-Flier?s team examined changes in gene activity occurring in mice fed a high-fat, low-carb diet for 30 days. Their comprehensive genetic screen of the animals, which lost weight on the special diet, turned up FGF21.

We saw a dramatic increase in FGF21 in the livers of the mice [on the diet], she said. We thought, ?Maybe there is something to this.?

Through further experimentation, the researchers found that liver and circulating levels of FGF21 increase in mice in response to both a low-carb, high-fat diet and fasting. Moreover, the hormone declined rapidly when fasted animals were fed again. In mice unable to produce FGF21 in their livers, the special diet resulted only in fatty liver, high blood lipids, and reduced blood ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism.

Meanwhile, Kliewer?s group identified the FGF21 endocrine hormone as a mediator of peroxisome proliferator-activated receptor (PPAR). Scientists have known that PPARcontrols fats? use as an energy source during starvation. In addition, some drugs that lower bad cholesterol work by targeting PPAR

Kliewer?s group showed that FGF21 is induced directly by PPAR in liver in response to fasting in mice. FGF21 in turn stimulates lipid breakdown in white adipose tissue and ketone body production in the liver. They unexpectedly also found that FGF21 led the animals to reduce their physical activity and made them more sensitive to entering torpor, a short-term, hibernation-like state.

In addition to altering their fuel sources, many small mammals conserve energy when food is scarce by undergoing periodic bouts of torpor, Kliewer explained.

When you step back, the whole thing makes sense, he 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.

The two studies together lead to an obvious possibility that FGF21 accounts for the proposed positive effect of the Atkins diet?including weight loss and an increase in ?good? cholesterol, Kliewer continued.

The degree to which the physiological effects of a ketogenic diet in humans mimic those seen in mice remains to be determined, Maratos-Flier added. She intends to examine FGF21 levels in humans after a few days on the Atkins diet, she said.

Either way, such low-carb, high-fat diets aren?t likely to work for everyone.

It may be that some people are more likely to turn on FGF21 than others, Maratos-Flier said. In obese individuals, for example, high insulin levels may interfere with the liver hormone, she said.

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