The obesity epidemic and how to beat it
This special mini-series tells you the latest on how metabolic interventions can make genes work to slim you down. This series was first published in Science and Society 21
Dr. Mae-Wan Ho traces the tangled paths of how diet affects metabolism affects gene transcription affects metabolism
It has long been known that a high-carbohydrate diet stimulates the synthesis of fatty acids and induces the transcription and expression not only of all the enzymes needed to make fatty acids, but also the enzymes breaking down glucose into the necessary building blocks for making all kinds of fat.
It appears that two distinct transcription factors are involved in providing the signals for making fats. Transcription factors bind to promoters of genes to boost transcription and hence gene expression. One transcription factor, SREBP-1c (Sterol Response Element Binding Protein), is stimulated by insulin, and binds to the SRE (Sterol Response Element) in the promoter region of genes encoding key enzymes that make cholesterol.
A second element, the carbohydrate response element, ChoRE, is involved in the transcription of fat-making enzymes after stimulation by high glucose in the absence of insulin. ChoRE sits in the promoters of enzymes involved in making other fats.
Two years ago, the research team headed by Kosaku Uyeda in the Dallas Veterans Affairs Medical Centre and Department of biochemistry, University of Texas in the United States, purified the protein that binds to the ChoRE in the promoter of the gene encoding liver pyruvate kinase from the livers of 800 rats that had been fasted and then refed a high-carbohydrate diet. This ChoRE binding protein (ChREBP) contains amino-acids in certain positions of the polypeptide chain that can be phosphorylated (accepting a phosphate group) by protein kinase A. Adding a phosphate group to serine in position 196 inhibits the protein from entering the nucleus, and adding a phosphate group to the threonine in position 666 inhibits its binding to the liver pyruvate kinase promoter site, both of which prevent transcription of the genes involved.
It has been known for a long time that cholesterol in the diet suppresses cholesterol synthesis in the body, mediated through feedback inhibition of SREBP production.
Feeding fat also inhibits carbohydrate metabolism, and the chain of biochemical events have been worked out by Uyeda’s group. Fatty acids are activated by ATP (adenosine triphosphate, the major energy intermediate in biochemical reactions) in a reaction that produces AMP (adenosine monophosphate). Thus, an increase in fatty acids boosts the level of AMP. AMP stimulates a protein kinase to phosphorylate ChREBP thereby inhibiting it from binding to its promoter site, preventing gene transcription.
Feeding high carbohydrate diet has the opposite effect on ChREBP, in that it activates the protein to enter the nucleus and to bind to its promoter site, thus enhancing transcription. Uyeda’s group has published new findings on how this is achieved, via the sugar phosphate, xylulose 5-phosphate, an obscure terminal player in the hexose monophosphate shunt, a side branch from the main glycolytic pathway that breaks down glucose.
The enzyme phosphofructokinase (PFK) sits at the intersection of the glycolytic pathway and the hexose monophosate shunt. Its activity is controlled in liver by the concentration of the metabolic molecule fructose-2,6-diphosphate, which stimulates PFK to proceed along the glycolytic pathway that eventually supplies all the building blocks for making fats.
Fructose-2,6 diphosphate is produced and destroyed by the same enzyme that catalyses both the forward and reverse reactions. The kinase activity, which makes fructose-2,6-diphosphate from fructose-6-phosphate by adding a phosphate group, is inhibited, while the phosphatase activity, which removes phosphate to regenerate fructose-6-phosphate, is activated by a cyclic-AMP dependent protein kinase that donates a phosphate group to the enzyme itself.
(Phosphate groups coming on and off small molecules and especially so, big molecules like enzymes and transcription factors, is the most common way to change their activities, as biochemists have been finding out for some decades now.)
A high-carbohydrate diet stimulates the kinase activity of this enzyme via a specific protein phosphatase (PP2A) that removes a phosphate group from the enzyme. PP2A itself is activated by, yes, xylulose-5-phosphate.
In the latest report from Uyeda’s group, PP2A and others in the same family, turn out to be agents that also activates ChREBP (by removing phosphate from it), so that it can enter the nucleus and bind to its promoter sites. Though their action on ChREBP, PP2A and family members are involved in promoting the transcription of a host of genes that make fats out of carbohydrates.
This must be one of the most heroic and sustained feats of scientific sleuth in our time. The group has hunted down all the culprits responsible for integrating the major metabolic pathways and gene transcription, showing how changing one’s diet appropriately can make metabolic sense. It is definitely not all in the genes.
Genes don’t determine our fate. Metabolic intervention can do wonders, for genes are at least as much the servants as masters of experience.
Article first published 12/02/04
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