http://www.rsc.org:80/chemistryworld/News/2007/June/05060702.asp

'Atkins hormone' discovered
05 June 2007

They are loved and endorsed by celebrities and dismissed as an unhealthy diet craze by critics. But 'low carb', high protein and high fat diets have proven their metabolic worth: scientists in the US have discovered a fat-burning role for a specific hormone stimulated by these eating regimes. The work has also raised the intriguing question of whether the Atkins diet could make you live longer.
A group of researchers led by Steven Kliewer at Southwestern University in Dallas, Texas found that a growth hormone called fibroblast growth factor 21 (FGF21) stimulates fat metabolism in the liver.

At the same time, Eleftheria Maratos-Flier and her colleagues from Boston University found that a ketogenic diet, low in carbohydrates and relatively high in fat, stimulated the production of this hormone. Both studies are published simultaneously in Cell Metabolism.

'It was one of those serendipitous discoveries,' Kliewer told Chemistry World. 'We were studying receptors in the liver that are activated by fatty acids, and we found that the receptors, called PPAR, regulate the hormone FGF21, so we went on to study what FGF21 does.'

Kliewer's treated mice with FGF21, either by genetic modification or direct injection, and said that it made the animals look like they were starving. 'It turned on a starvation response, even when the animals were feeding. They switched from using carbohydrates to fat stores as an energy supply,' he said.

Maratos-Flier's group fed their mice a high fat, low carbohydrate diet for 30 days and found that levels of FGF21 increased.

This biochemical deception, causing the body to burn fat even when on a high fat diet, is a weight loss method made famous by Robert Atkins, who died in 2003. Such diets are called ketogenic because, without a source of carbohydrate to produce energy, fats or lipids are metabolised, producing ketones as a replacement fuel.

Starving to stay younger

Although previous work linked FGF21 to metabolism, Kliewer's work illustrates its fat burning function for the first time. 'This is one of the most exciting things I've ever worked on,' he said. 'Starvation and restricted diet are linked to some fascinating physiology including longevity. In the long term, I would like to investigate the role of FGF21 in ageing, since caloric restriction has been linked to an extended life span in many species.'

David Moore from Baylor College of Medicine in Houston, Texas described the link between calorie restriction and longevity as a 'tantalising' research area.

'When you starve an overweight body, you see many metabolic benefits, including increased fat metabolism, some of which could be mediated by FGF21,' Moore told Chemistry World. 'There was a study described at a conference recently, where a morbidly obese child undertook a medically supervised 300 day fast. He lost half his body weight and was reported to be physically fine.'

Moore pointed out that in all species tested so far, including worms, birds, rodents and dogs, restricting calorie intake leads to a longer life span (see Chemistry World, May 2007, p24). But a long term longevity study in humans is a huge practical challenge.

Eric Ravussin from Pennington Biomedical Research Center in Louisiana has pinpointed a number of biomarkers for ageing that he says could start to answer the question of whether a ketogenic diet or FGF21 increases life span. 'This type of diet or this hormone could provide a surrogate for calorie restriction,' he suggested.

Interesting inasmuch as this shows that you can't always explain all your results on the basis of the hormones and biochemsitry that is currently known. Whether this particular hormone is significant, remains to be seen. Probably others are out there, not yet discovered or poorly understood.

I don't think there is quite the tight relationship between LC and CR that these people think there is. I see two clear relationships between LC and CR. The first is that LC simply results in a lower calorie intake on an ad libitum diet. The second, is that both were a common part of man's diet and as such, are how we are adapted to eat. Other than that, I don't know that there is a real parallel here. I think LC and CR have mostly a separate set of metabolic consequences, both good in terms of health and longevity. I think CR is trickier and tougher to execute properly. LC, on the other hand, is an easier way to get healthier. I'm sure a combination of the two is probably optimal, I just haven't been able to make the committment and don't foresee doing it. But you never say never.

Well said.

Discovering "Hormones" is really just pharma-funded news events that are meant to prep the public that new pills may be coming.

There ain't no magic pills.

LC diets also teach people what they are eating. It is an important lesson to walk into a variety store and attempt to eat Low Carb. Then it hits you, "All I can eat here is Diet Coke and a beef jerky !". "Maybe I shouldn't come here".

Another story.
http://www.medpagetoday.com/Primary.../tb/5867?blg=k1

Hormone Linked to Stored Fat Could Explain Atkins Diet

By Michael Smith, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
June 06, 2007

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 research by the Boston group was supported by the National Institutes of Health and Takeda Pharmaceuticals. The researchers did not report any potential conflicts.

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.

..I think an intermittent fasting for 24 hours low carb for a year (or a lifetime..) would have been a better option for the kid. In other words, they starved the kid for a year. Poor kid.

I have fasted for 20 days several times in my life (water only) and can say that the feeling I have in Ketosis is almost identical to being on a fast. During those fasts I was active (did 5 miles a day on a treadmill) and felt the eurphoric feelings of ketogenisis.
This sounds like a link to me.... cool after 20 years...

why do they need to develop a drug? The solution simply lies in allowing the body to function as it naturally does when eating a LC/mod protein/high fat diet. As shown here: The body does it all by itself without any "intervention" by expensive medications. I say if your body will correct itself, don't mess with it. Leave it alone to get on with the business of burning fat....

Such a long fast, surely they gave him all the non-caloric nutrients the body needs?

Now that I know about atkins, I wouldn't want to take a drug to lose weight.

Lots of Fat, No Carbs--And the Right Hormone
By Krista Zala
ScienceNOW Daily News
6 June 2007

Whether a high-fat, low-carbohydrate diet melts your kilos away may hinge on your propensity to produce a single hormone--no matter how diligently you stick with the cheese. Two studies published in the June issue of Cell Metabolism clarify how a protein regulates fat burning when the body switches from carbohydrates to fat reserves for energy. The findings could one day help people struggling with type 2 diabetes, obesity, or other metabolism disorders.

When the body is fed lots of fat and few carbohydrates--an Atkins diet without the protein--it gears into starvation mode. Without an easily digestible dose of sugar and starch, the body taps its fat stores, shipping fat molecules from the adipose tissue to the liver, where they're broken down into ketones (which is why researchers call it a ketogenic diet). Eleftheria Maratos-Flier, an endocrinologist at Beth Israel Deaconess Medical Center in Boston, wondered what triggered the change.

She and her colleagues fed mice either a ketogenic or a regular diet for 30 days. Liver levels of FGF21, a protein with a known role in metabolism, jumped in mice fed a ketogenic diet, then plunged once they ate a regular meal. Intrigued, the researchers engineered transgenic mice that could not make enough of the hormone and fed them the same diet. "Their liver blew up with fat," says Maratos-Flier. Without the ability to burn triglycerides, cholesterol, or free fatty acids, the result was "mouse foie gras," she quips. This shows that the body relies on the hormone in switching to breaking down fat.

The hormone flicks a switch in behavior, too. In a separate study, Steven Kliewer, a molecular biologist at the University of Texas Southwestern Medical Center in Dallas, and colleagues fed normal mice and transgenic mice that overproduce the hormone a regular diet, then starved them for a day. Normal mice didn't change their habits. But body temperature of transgenic mice plummeted and they stopped moving, entering into a hibernationlike state called torpor. "All of this was completely unexpected," he says. "They looked like they were starved, even when they were fed."

The hormone's knack for revving up fat metabolism and weight loss, added to earlier evidence that it makes blood sugar levels drop, may lead to treatments for people with type 2 diabetes or obesity, Kliewer says. Maratos-Flier's lab hopes to explore whether obese mice given the hormone will get lean again.

Studies like these two will eventually help tailor diets to people based on their physiology and genes, says obesity researcher Randy Seeley of the University of Cincinnati, Ohio. But he cautions that mouse and human livers aren't the same; what's more, whereas Atkins-like diets seem to work in humans because they eat less, mice lose the weight through exercise. That makes him skeptical that the studies will apply directly to humans.

It seems that this study is attracting attention and may cause Atkins' diet to regain some of its lost popularity. Here is another article:

Hormone Found In Liver Helps To Induce Ketosis, The Unique Metabolic State Brought About By Low-Carbohydrate Diets

Article Date: 11 Jun 2007 - 4:00 PDT

http://www.medicalnewstoday.com/med...hp?newsid=73284

from the above article, proving that calories are not created equal and the calories in and calories out theory is bupkus....

...and I'll bet that insulin or high blood sugar inhibits FGF21.

If true, that alone would indicate that low-carb can not be an abnormal 'just like starvation' diet. It's the way the body was meant to be fueled long-term.