Sometimes you get lucky and fall on something you wasnt actually looking for. I was doing some research on the possible relationship between FoxO1 and ChREBP in the liver ( more on that possible link in a moment ) when I found this little theory paper.
High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload.
If anyone can link the full text id be interested ( its behind a paywall ), but anyway, the abstract tells you the gist of this guys thinking. Recall that ChREBP is a transcription factor activated by high concentrations of glucose in the liver.
One of the important jobs of ChREBP is go into the nucleus and start spitting out enzymes that convert carbs to fat. ( like fatty acid synthase ). However in the abstract we learn that ChREBP also codes for glucose 6-phosphatase, and this enzyme in turn, stimulates production of Glucokinase regulatory protein ( GKRC ).
In turn, GKRC inhibits liver Glucokinase.
Remember that the activity of glucokinase determines liver glucose uptake because it relives the concentration gradient of the GLUT2 receptors on the liver, allowing more glucose to flow into the liver from outside. Glucokinase is also a target for insulin and GLP-1, and the activation of glucokinase by GLP-1 is probably a primary way that GLP-1 helps diabetics.
Sorry I didnt mean for this to get so technical!
So , to condense this guys theory, he is saying that hepatic IR is caused by ChREBP inhibiting glucokinase.
But I think there may be slightly more to it than that, I also found this paper which says that FoxO1 inhibits ChREBP.
From the last post we saw that FoxO1 codes for enzymes for gluconeogensis, but, ChREBP codes for enzymes that convert carbs to fat. Its probably not a good idea to have both FoxO1 and ChREBP running at the same, because the glucose you make from FoxO1 will get converted to fat by ChREBP? Which just means your going around in circles.
FoxO1 is suppose to mediate the fasting state, where blood glucose concentration is constantly replenished and muscles become insulin resistant to conserve glucose for the brain during.
My theoretical speculation is this, if the level of ChREBP is the liver is elevated due to high carbohydrate consumption aswell as frequent consumption, does this inadvertently force FoxO1 to be higher? Is FoxO1 hyper-active BECAUSE ChREBP is elevated? And yes, ChREBP is elevated in the liver of obese people as pointed out by Lucas.
Inhibition of ChREBP in ob/ob mice improves insulin resistance while deficiency ChREBP actually prevents obesity in ob/ob mice. Is there a connection between leptin and ChREBP?
Yes!
Leptin activates AMPK and in turn AMPK inhibits the activity of ChREBP. It is well reported that Metformin activates AMPK, so its looks like Metformin may also inhibit ChREBP, this is probably where the ability of Metformin to improve insulin sensitivity stems from. In that last study above they also report that vinegar supplementation ( 30ml per day ) slightly improved weight loss, acetic acid converts to acetate which activates AMPK and thereby inhibits liver ChREBP. The relation appears to be dose-dependent, so more vinegar = more weight loss. Up to 90ml per day was deemed safe.
Anyway, im quite convinced that it is liver ChREBP that causes hepatic insulin resistance. And if metabolic syndrome is the manifestation of hepatic insulin resistance then this implies liver ChREBP is the cause of metabolic syndrome.
Urgh, it IS the bloody carbohydrates!
I think im just about done here..............
Monday, 12 November 2012
Saturday, 10 November 2012
Is FoxO1 making you fat?
I got this link from a comment that George posted.
FoxO1 is a transcription factor ( you can see a video here of what it does ). Its job is to enter the nucleus in cells, read the DNA sequence it binds to, and start churning out the peptides that that particular DNA sequence codes for. And it just so happens that FoxO1 codes for the enzymes involved in gluconeogenesis.
These particular enzymes are rate-limiting unfortunately, I.E. they determine the rate at which the process happens. The more of these enzymes you have active, the higher your rate of hepatic glucoenogenesis. So, loosely speaking we have........
High FoxO1 activity -> lots of gluconeogenic enzymes floating around -> high rate of hepatic glucose production.
The problem is further compounded by the fact that FoxO1 seems to cause insulin resistance in muscle, it causes muscle to start up-taking fat and burning it and ignore glucose oxidation, this will result in decreased muscle glucose uptake aswell. Recall that muscle is the primary site for peripheral glucose disposal after a meal. All the glucose in your blood after you eat a potato has to go somewhere, and if it doesnt get disposed of in muscle because of a high FoxO1 activity making muscle insulin resistant, it probably ends up being disposed of in adipose tissue.
Disposing of alot of glucose in adipose tissue promotes fat tissue growth ( obesity ). Remember the high levels of leptin seen in fat people being atleast partly a consequence of glucose going down the lipogenesis pathway inside adipocytes? Where did all that glucose come from anyway?
Answer: it got rejected from muscle because muscle is insulin resistant because of a high FoxO1 activity.
Suddenly it all seems so clear, the idea that fat tissue growth "protects" you from diabetes would appear to be a very real phenomenon. Actually, I wouldnt really say fat tissue growth is "protecting" you, but rather it is masking the problem. The fat tissue is sucking up all the glucose that isnt being disposed of in muscle.
FoxO1 is where we finished with the recent Lustig paper, In it, Lustig talks about selective hepatic IR, where insulin is suppose to suppress gluconeogenesis after eating a potato, insulin is suppose to stop FoxO1 from entering the nucleus and therefore stop it from doing its job of making gluconeogenic enzymes during a time when blood glucose is naturally elevated because we've just eaten some glucose. The problem seen in metabolic syndrome is that insulin fails to properly suppress FoxO1 in response to potato eating.
It is also likely that hyper-activity of FoxO1 is causing the elevated fasting blood sugar in MetSyn.
The question that Lustig couldnt answer, and the question that may well be the answer to the whole diabesity epidemic is, why is the FoxO1 transcription factor so hyper-active?
FoxO1 is a transcription factor ( you can see a video here of what it does ). Its job is to enter the nucleus in cells, read the DNA sequence it binds to, and start churning out the peptides that that particular DNA sequence codes for. And it just so happens that FoxO1 codes for the enzymes involved in gluconeogenesis.
These particular enzymes are rate-limiting unfortunately, I.E. they determine the rate at which the process happens. The more of these enzymes you have active, the higher your rate of hepatic glucoenogenesis. So, loosely speaking we have........
High FoxO1 activity -> lots of gluconeogenic enzymes floating around -> high rate of hepatic glucose production.
The problem is further compounded by the fact that FoxO1 seems to cause insulin resistance in muscle, it causes muscle to start up-taking fat and burning it and ignore glucose oxidation, this will result in decreased muscle glucose uptake aswell. Recall that muscle is the primary site for peripheral glucose disposal after a meal. All the glucose in your blood after you eat a potato has to go somewhere, and if it doesnt get disposed of in muscle because of a high FoxO1 activity making muscle insulin resistant, it probably ends up being disposed of in adipose tissue.
Disposing of alot of glucose in adipose tissue promotes fat tissue growth ( obesity ). Remember the high levels of leptin seen in fat people being atleast partly a consequence of glucose going down the lipogenesis pathway inside adipocytes? Where did all that glucose come from anyway?
Answer: it got rejected from muscle because muscle is insulin resistant because of a high FoxO1 activity.
Suddenly it all seems so clear, the idea that fat tissue growth "protects" you from diabetes would appear to be a very real phenomenon. Actually, I wouldnt really say fat tissue growth is "protecting" you, but rather it is masking the problem. The fat tissue is sucking up all the glucose that isnt being disposed of in muscle.
FoxO1 is where we finished with the recent Lustig paper, In it, Lustig talks about selective hepatic IR, where insulin is suppose to suppress gluconeogenesis after eating a potato, insulin is suppose to stop FoxO1 from entering the nucleus and therefore stop it from doing its job of making gluconeogenic enzymes during a time when blood glucose is naturally elevated because we've just eaten some glucose. The problem seen in metabolic syndrome is that insulin fails to properly suppress FoxO1 in response to potato eating.
It is also likely that hyper-activity of FoxO1 is causing the elevated fasting blood sugar in MetSyn.
The question that Lustig couldnt answer, and the question that may well be the answer to the whole diabesity epidemic is, why is the FoxO1 transcription factor so hyper-active?
Subscribe to:
Posts (Atom)