Study may help explain success of low-carb diets

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Interesting. I wonder what role the FGF21 hormone produced in the liver

might play in CR.

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Study may help explain success of low-carb diets

Dallas: In mice, hormone triggers body to rely on fat, not sugar, for

fuel

http://www.dallasnews.com/sharedcontent/dws/news/localnews/stories/DN-

utswhormone_06met.ART.State.Edition1.440ab8c.html

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Hi All, The not pdf-availed paper abstracts are below, but I failed to save the text of Jeff's web site and it now requires a membership to the newspaper. Cheers, Al Cell Metab. 2007 Jun 6;5(6):426-437.Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARalpha and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States.Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E.PMID: 17550778 Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARalpha. Importantly,

adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone. Cell Metab. 2007 Jun;5(6):415-25.Endocrine Regulation of the Fasting Response by PPARalpha-Mediated Induction of Fibroblast Growth Factor 21.Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA.PMID: 17550777 Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the

utilization of fat as an energy source during starvation and is the molecular target for the fibrate dyslipidemia drugs. Here, we identify the endocrine hormone fibroblast growth factor 21 (FGF21) as a mediator of the pleiotropic actions of PPARalpha. FGF21 is induced directly by PPARalpha in liver in response to fasting and PPARalpha agonists. FGF21 in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF21 also reduces physical activity and promotes torpor, a short-term hibernation-like state of regulated hypothermia that conserves energy. These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.jeffp54252 <jeffp54252@...> wrote: Interesting. I wonder what role the FGF21 hormone produced in the liver might play in CR.----------------------------------------------------------Study may help explain success of low-carb dietsDallas: In mice, hormone triggers body to rely on fat, not sugar, for fuelhttp://www.dallasnews.com/sharedcontent/dws/news/localnews/stories/DN-utswhormone_06met.ART.State.Edition1.440ab8c.html

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Scientists: Hormone could shed new light on weight loss 08:00 AM CDT on Wednesday, June 6, 2007By SUE GOETINCK AMBROSE / The Dallas Morning Newssgoetinck@... A recently discovered hormone is instrumental in helping the body switch its fuel source from sugar to fat, new research from Dallas and Boston scientists suggests. The findings could explain some aspects of the success of low-carb diets, provide new ideas for weight loss drugs, and one day help doctors recommend scientifically designed, personalized eating plans. Researchers caution the new studies are done only on lab mice. “The open question is about how this applies to humans,” said neuroscientist Randy Seeley, associate director of the Obesity Research Center at the University of Cincinnati, who was not involved in the

research. But, he added, “this definitely puts [the hormone] on the map as potential targets that companies will begin studying.” The Dallas and Boston scientists studied a hormone called FGF21 that’s produced in the liver. Scientists already knew the hormone helped lower body weight, cholesterol and lipid levels in the blood. But they knew little about how it worked. To find out, the Dallas scientists, led by Kliewer and Mangelsdorf of UT Southwestern Medical Center, studied the hormone in both fed and fasted mice. Fasting caused hormone levels to soar. Further experiments pinpointed the biochemical trigger for the hormone; the scientists also found that the hormone signals the liver to burn fat that had been stored elsewhere in the body. The Boston scientists found that both fasting and a high-fat, low-carb diet, also ramp up levels

of FGF21. At first, that may seem counterintuitive, said Dr. Eleftheria Maratos-Flier, the investigator at Beth Israel Deaconess Medical Center who led the Boston study. But it’s not. “The common theme is that if you fast, you need to rely on stored fat,” she said. “If you’re eating a low-carb diet that’s high in fat, you need to rely on fat.” Articles describing both groups’ research appear in the latest issue of the journal Cell Metabolism. One of the next steps, Dr. Maratos-Flier said, is to check whether the hormone also goes up in people eating a low-carb diet, or in people who are fasting. If all the findings in mice also apply to people, she said, the hormone could explain why people on low-carb diets don’t have extremely high levels of fat in their bloodstream. It could be, she said, because the hormone ensures that fat is burned. The UT Southwestern

scientists also studied mice that were genetically engineered to constantly produce high levels of the hormone. The researchers found that fasting drove these mice into a “torpor,” or a hibernation-like state. In this state, the mice are less active and their body temperature drops. “We think we’ve come across one of the key factors driving animals into hibernation,” Dr. Kliewer said. The situation in people will obviously be a little different. “We need to find out how all this works in people,” he said. “People don’t go into hibernation.” Scientists said any medical impact of the new studies is still a long way off. Human studies are just beginning. Some of the many lines of work will include checking what the hormone does in people, whether it’s possible to use the hormone as a biological readout of a person’s metabolic state, and whether using

the new information can help with scientifically designed diets. Scientists will also investigate whether the hormone or other related molecules can be turned into medications to promote weight loss or lower lipid levels in the blood. S till, Dr. Seeley noted, the discovery of the hormone alone shows how much scientists still have to learn about why the body burns or stores fat. “ The modern era of studying obesity started in 1994,” he said. “Do we have good treatments yet? The answer is no.” Other UT Southwestern researchers who participated in the study include Takeshi Inagaki, Dutchak, Guixiang Zhao, Xunshan Ding, t Gautron, Vinay Parameswara, Esser, Elmquist, Gerard, Burgess and Hammer. Cell Metab. 2007 Jun 6;5(6):426-437.Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARalpha and Is a

Key Mediator of Hepatic Lipid Metabolism in Ketotic States.Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E.PMID: 17550778 http://tinyurl.com/2nnj2d Cell Metab. 2007 Jun;5(6):415- 25.Endocrine Regulation of the Fasting Response by PPARalpha-Mediated Induction of Fibroblast Growth Factor 21.Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA.PMID: 17550777 http://tinyurl.com/2slq5w Cheers, Al

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