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Medical News Today
Hormone Found In Liver Helps To Induce Ketosis, The Unique Metabolic State Brought About By Low-Carbohydrate Diets
11 Jun 2007
Over the past several years, animal studies have shown that high-fat, low-carbohydrate "ketogenic" diets cause
demonstrable changes in metabolism and subsequent weight loss. Now, researchers at Beth Israel Deaconess Medical
Center (BIDMC) have identified a key mechanism behind this turn of events. Their findings, which appear in the
June 2007 issue of Cell Metabolism, demonstrate that a liver hormone known as FGF21 is required to oxidize fatty
acids - and thereby burn calories.
"When the diet is extremely low in starches and sugars, blood sugar levels drop substantially so that muscle and
brain have to turn to alternative fuels," explains senior author Eleftheria Maratos-Flier, MD, an investigator in
the Department of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard
Medical School. "Consequently, fatty acids are broken down in the liver and converted to ketones, which then serve
as a major fuel source."
Known as ketosis, this metabolic state is characterized by extremely low insulin levels, as would occur during
periods of fasting or starvation or while consuming a low-carb diet, such as the popular Atkins diet model.
For the past several years, Maratos-Flier's laboratory has been studying the physiologic states of animals
consuming various types of diets -- including standard "animal chow" diets and diets moderately high in both fats
and carbohydrates, as well as ketogenic diets. And she has found through her experiments that even though mice
are fed exactly the same number of calories, the composition of the calories causes them to gain weight in
"The differences in weight gain reflect differences in metabolic rates," she explains. "These, in turn, result
in hormonal changes that lead to different disposition of the calories."
In this latest paper, Maratos-Flier and colleagues studied mice that had been fed a ketogenic diet high in both
saturated fat and unsaturated fat and practically devoid of carbohydrates.
"Despite the high fat content of this diet, the study animals maintained normal levels of circulating lipids,"
she explains. "We wanted to learn what factors might be responsible for creating this state in which consumed
calories were being burned off in the liver rather than being stored as fat."
Because the physiologic changes in the animals didn't appear to be explained by typical hormonal regulators -
neurotransmitters that normally regulate appetite - the researchers set out to identify which genes were unique
to this ketogenic phenotype, exploring the possibility that hepatocytes were playing an active role in the process.
And, using micoarray gene analysis, they discovered that their hunch was correct: FGF21, a liver-derived fibroblast
growth factor gene, was significantly increased in the mice that had been fed ketogenic diets.
"FGF21 had previously been identified as a potential metabolic regulator by scientists at Eli Lilly, who showed that
transgenic mice that overexpressed FGF21 were protected from diet-induced obesity, had smaller fat cells and had
more brown adipose tissue,"says Maratos-Flier. "But little was actually known about FGF21's physiologic roles.
Working with Jeffrey Flier's lab, we were able to show that FGF21 is essential for fatty acid oxidation."
Furthermore, she explains, when FGF21 was inhibited, the mice developed a massive accumulation of fat in the liver
and an extreme increase in circulating lipids.
A second study by Maratos-Flier and colleagues published in the June 2007 issue of the American Journal of
Physiology further elucidates the unique metabolic changes that occur with the consumption of a ketogenic diet.
"Although the purpose of both of these studies was to glean insights into metabolic physiology, our findings
suggest that increased levels of FGF21 may be a potential mechanism behind low-carbohydrate diets' beneficial
properties when it comes to lipid metabolism," says Maratos-Flier. "Diets that limit carbohydrates and eliminate
transfats, and at the same time emphasize fiber and good fats, appear to be healthiest, especially among
individuals who are predisposed to developing diabetes."
This study was supported, in part, by grants from the National Institutes of Health and from Takeda Pharmaceuticals.
Coauthors include BIDMC investigators Michael Badman (lead author), Pavlos Pissios, Adam Kennedy and Jeffrey S.
Flier, MD; and George Koukos of Boston University School of Medicine.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School
and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is
clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer