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Old 06-08-2007, 07:55 AM   #1
Steve Shafley
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Join Date: Oct 2006
Posts: 1,285
Default New studies

I have the full papers on these:

Cell Metab. 2007 Jun;5(6):405-7.
FGF21: A Missing Link in the Biology of Fasting.
Reitman ML.

Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA.

A sufficient energy supply is essential for life; consequently, multiple mechanisms have evolved to ensure both energy availability and conservation during fasting and starvation. Two reports in this issue of Cell Metabolism (Badman et al., 2007; Inagaki et al., 2007) demonstrate that FGF21, a circulating protein produced in the liver in response to the PPARalpha transcription factor, is a "missing link" in the biology of fasting, inducing adipose tissue lipolysis, liver ketogenesis, and metabolic adaptation to the fasting state.
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.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.
Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States
Michael K. Badman, Pavlos Pissios, Adam R. Kennedy, George Koukos, Jeffrey S. Flier, and Eleftheria Maratos-Flier,*
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston,
MA 02215, USA
Department of Biochemistry, Center for Advanced Biomedical Research, Boston University School of Medicine,
700 Albany Street, Boston, MA 02118, USA
*Correspondence: emaratos@bidmc.harvard.edu
DOI 10.1016/j.cmet.2007.05.002

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 PPARa.
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.
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Old 06-08-2007, 08:25 AM   #2
Daniel Miller
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Location: Missouri
Posts: 60

With the knockdown and the fact that PPAR-alpha is the molecular target for the fibrate dyslipidemia drugs, these studies really zero in on mechanisms.

I'm psyched to read the studies and see how they substantiate beyond knockdowns. I'm imagining lots of westerns at different time intervals for both KD mice and mice fed super high Cho-diets. Can't wait to see what other methods they use. I'd be curious to know if there will be an (for lack of a better term) 'intermediate' diet for the mice ie one in-between a KD and high-Cho diet.

Thanks for the link. I would have missed this! THIS BOARD IS GREAT!
“Our doubts are traitors,
And make us lose the good we oft might win,
By fearing to attempt.”
-William Shakespeare, Measure for Measure
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Old 06-08-2007, 08:27 AM   #3
Daniel Miller
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Join Date: Feb 2007
Location: Missouri
Posts: 60

It's also nice to see interesting research coming from Merck. I'm guessing they've already done what the need to do in terms of development.
“Our doubts are traitors,
And make us lose the good we oft might win,
By fearing to attempt.”
-William Shakespeare, Measure for Measure
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Old 06-08-2007, 04:12 PM   #4
Robb Wolf
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Nice stuff Steve, Thank you.

Looking for drug targets is nice but it is missing the downstream gene alterations of simply BEING in ketosis, to say nothing of the improved delta-G of ATP hydrolysis and factors associated with mitigating glycolysis.

Props for them trying however...otherwise this research would never happen.
"Survival will be neither to the strongest of the species, nor to the most intelligent, but to those most adaptable to change."
C. Darwin

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Old 06-08-2007, 09:21 PM   #5
Steve Shafley
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Join Date: Oct 2006
Posts: 1,285

Robb, I've got PDF of the studies if you want them...either PM or email me.
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