Monosodium glutamate stimulates secretion of GLP-1

I found this cute little study today, if you follow the link from pubmed and click on the PDF you can get the full text for free.

In the study they made people drink test meals containing alot of carbohydrate and protein, and added either 2g MSG or some salt to them. The group that drank the test meal spiked with MSG had reduced postprandial glycemia ( good ) and significantly increased GLP-1 secretion ( good )

How quaint!

Ive blogged thousands of times on the beneficial effects of GLP-1 with respect to body weight control, glucose tolerance etc so im not gonna bother rehash its merits here, suffice to say that I think all the controversy surrounding MSG is overblown and false. Ive never had a problem with it myself, and I absolutely love things like parmesan cheese, soy sauce, marmite etc etc.

So does this mean consuming MSG may actually be beneficial? MAYBE. Indulge in self-experimentation is what I would say.

suppversity also has a very comprehensive post on MSG.

I must be mad to think this.... ChREBP

Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.

• ChREBP plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase
• Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates.

Obviously we need to be careful here because we are dealing with ob/ob mice, but the message is clear, ChREBP induces lipogenic gene expression. No doubt this is partly responsible for the fatty liver in ob/ob mice as demonstrated in the last bullet point above. The point I want to deduce however is that, if ChREBP favors "lipid accumlation" in the liver, what do you think ChREBP is doing in the adipose tissue? Surely it must favor lipid accumlation there aswell??!  I.E.    OBESITY.

I must be mad to think this right?

The only conundrum I have to contend with is the study in Lucas Tafur's post which showed that obese people have reduced levels of ChREBP in adipose tissue compared to lean people. Such confusion! But perhaps this phenomenon is observed because the obese people are already fat. It should stand to reason that for a given particular individual, their potential to get even fatter is steadily reduced as they fatten up. In this situation it makes sense that adipocyte ChREBP would decline as they become obese.

We also have the notion from the study I linked in my previous post, this one, they showed that per adipocyte, glucose uptake is less in obese people compared to lean people. BUT, and here is the punchline, this is over-compensated for by the fact that obese people have more total fat tissue. This fits in with the above idea that adipocyte ChREBP is reduced in obese compared to lean.

Something else just clicked this morning aswell..... remember how I posted that fat issue growth drives over-eating, and NOT the other way around? ( 1 ) Well check out this study again.....what does Troglitazone do? We established last post that it most likely encourages fat tissue growth, no wonder the people taking Troglitazone reported increased hunger. duh!

I want to bookmark some studies below that I will look into in the coming days. If I find something interesting ill make a post!

Hidden variant of ChREBP in fat links lipogenesis to insulin sensitivity.

A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism.

Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor alpha.

On the role of liver X receptors in lipid accumulation in adipocytes.

Adipocyte ChREBP

ChREBP is something that Lucas Tafur talked about here. His post is a good primer on the subject of ChREBP but beware its quite a technical post.

Anyway, to simply put it, ChREBP is how your body REACTS to dietary carbohydrate. The picture in Lucas's post is such a fantastic illustration of exactly what "life" is.

"life" is quite simply dead pieces of matter REACTING to their environment. The reaction is usually always predictable and the same, which is why I am a strong believer in determinisim and why I refute the idea of "free will". .Anyway, I stumbled on quite a few interesting things involving ChREBP and its quite likely that its one of the important technical things missing in Taubes's Carbohydrate Insulin Hypothesis.

Troglitazone is an anti-diabetic drug that is used to "treat" diabetes. Essentially what this drug does is instruct your adipose tissue to get very good at sucking up blood sugar and converting it to fat, thereby helping to control hyperglycemia  Troglitazone has the well known side affect of weight gain. But how exactly does Troglitazone enhance glucose disposal in adipose tissue? Well, either it enhances adipose tissue glucose uptake OR it promotes adipocyte differentiation ( or probably some combination of the two ). Initially I thought it was the first option, which lead me to search for studies which showed that Troglitazone increased leptin, since we already know leptin secretion is a product of carb to fat lipogenesis.

So if I could find a study that showed Troglitazone increased leptin that would be pretty good evidence that Troglitazone increased adipose tissue glucose uptake, but instead what I found was this. This study says that Troglitazone decreases leptin in patients with BMI less than 30 but leaves leptin unchanged in patients with BMI over 30. This leads me to the conclusion that Troglitazone works primarily by adipocyte differentiation, probably with some secondary affects of increased adipocyte glucose uptake.

However, one thing we can be sure of though is that Troglitazone increases adipocyte ChREBP. ( 1 ) And Troglitazone makes you fat. So.........anything else that increases adipocyte ChREBP likely also makes you fat........... what else increases adipocyte ChREBP? Yes baby thats right, glucose + insulin. Another point made by that paper is this.....

ChREBP expression in adipose tissue is not significantly affected by the diabetic state

Once again, this leads me to conclude that diabetes is a manifestation of the adipose tissue failing to expand to accommodate for increased glucose uptake, i.e. your adipose tissue does not want to act as a sink for excess blood sugar during hyperglycemia. On the other hand, if your adipose tissue is happy to expand and suck up excess blood sugar, youll get fat instead of getting diabetes.

BTW, maybe its just a coincidence that one of the downstream targets of ChREBP is fatty acid synthase, and that some cancer's are associated with over-expression of fatty acid synthase. Cancer is also associated with metabolic symdrome......... But yeh,.....anyway....... its probably all just a coincidence. Probably.

Now, for some funny reason, I cant seem to find this study in pubmed...

analyses of adipose tissue lysates revealed greater fatty acid synthase (FAS) and acyl-CoA carboxylase expression in the HC fed groups, suggesting increased de novo lipogenesis following HC consumption. Increased lipogenic protein expression was also associated with greater nuclear levels of carbohydrate-response element binding protein (ChREBP) in HC fed rats.

And here's a brand new study looking at ChREBP in fruit flies! ( 2 ) You dont need to read the study or even the abstract, because the title tells you everything you need to know.....

Mio/dChREBP coordinately increases fat mass by regulating lipid synthesis and feeding behavior in Drosophila.

Possible Mechanism for the Carbohydrate Insulin Hypothesis?

I have long observed that some sources of carbs tend to be more fattening than others, and that the degree to which the carb source spikes your blood sugar is also a very good indication for how fattening that carb source is. Given that there is such a thing as the "low-GI" diet lends credibility to this theory, atleast in part.

Glycemic Index broadly speaking is defined as how fast a particular carb source spikes your blood sugar. I think this is missing 1 key aspect however, although I dont have a glucose carbon tracer study on hand to prove this, but I suspect that in the case of high GI foods that the total amount of glucose entering circulation is also higher in addition to the speed at which it raises blood sugar. Foods that contain a high density of simple glucose molecules should likely be the worst for blood sugar control, and probably also obesity.

This quote is from the wikipedia page on glycemic index

Recent animal research provides compelling evidence that high-GI carbohydrate is associated with increased risk of obesity. In one study,[15] male rats were split into high- and low-GI groups over 18 weeks while mean body weight was maintained. Rats fed the high-GI diet were 71% fatter and had 8% less lean body mass than the low-GI group.

A higher amount of glucose entering circulation is a massive problem because hyperglycemia is toxic, it also puts immense pressure on the peripheral to act as a glucose sink in order to return to normoglycemia. The "peripheral" mainly consists of muscle and adipose tissue. I have already posted previously my theory that the high leptin seen in fat people is primarily a result of high-levels of the carb -> fat  pathway inside adipocytes. This is why carbohydrate density of foods is associated with high leptin, ( 1 ), because foods with a high density of simple glucose molecules simply results in more total glucose entering circulation.

More glucose entering circulation leads to more insulin leads to more glucose uptake by adipocytes leads to more lipogenesis pathway and finally leptin secretion.

As I posted on Wooo's blog here, my theory is that a high carbohydrate density and/or food that consists of mainly simple glucose molecules results in a high mass flow rate of glucose in the portal vein, this puts pressure on your liver to work "quickly" to handle all that glucose before it hits circulation. Through the activation of glucokinase, the liver uptakes the glucose through GLUT2 via simple concentration gradient. Due to physical limitations, there will obviously be a maximal rate at which glucokinase can phosphorylate glucose and thus maintain the concentration gradient.

But there is also the complication that some people secrete less glp-1 in response to carbohydrates, and since glp-1 also activates glucokinase, such people would have even more total glucose hit circulation when consuming high-GI foods. ( btw at present, no-one knows why some people secrete less glp-1 in response to carbs, the latest research says it has something to do with the high expression of UCP2 in the cells of the gut )

I am not alone in my theory that foods containing high concentrations of simple glucose molecules is inherently fattening, this research group is also onto it.... ( 2 ) They show that high-carb diets always leads to higher adiposity than isocaloric high fat diets. However the really interesting part was the change in adipose tissue gene expression, which included increased levels of GLUT4 on adipocytes. This fits in exactly with the idea that weight gain and adipose tissue expansion is an adaptive and protective measure initiated to protect you from diabetes. Actually, scratch that, it is an adaptive and protective measure to protect you from hyperglycemia.

Genes regulating glucose transport, glycolysis, fatty acid and triglyceride biosynthesis, desaturation and elongation, adipogenesis, and adipokines were affected by High-carb diets.

The adipose tissue literally changes its gene expression to accommodate for increased glucose uptake. Your adipose tissue "learns" to be very good at sucking up excess blood sugar. The same conclusion was reached by this group of researchers ( 3 ). To quote......

However, increased total fat mass provides a sink for the excess of glucose and compensates for insulin resistance.

I would like to speculate that reversing the obesity associated with excess carbohydrate consumption would involve undoing the change in gene expression in adipocytes, particularly that of increased GLUT4 utilization. Not eating a diet that aggressively spikes blood sugar could communicate to adipocytes that their increased GLUT4 expression is no longer needed. Another thing that comes to mind is anaerobic exercise,  its quite well known that anaerobic exercise improves body composition. I think that what may be happening is that the hypoglycemia challenges during such exercise send an additional signal to adipocytes that their increased GLUT4 expression is starting to actually become harmful. In response they may down-grade gene expression for GLUT4. ( ofcourse exercise also improves muscle glucose uptake so that is another mechanism by which glucose flux into adipocytes is reduced ).

Increased expression of GLUT4 on adipocytes promotes obesity ( 4 ).

So yes, I still believe in the carbohydrate insulin hypothesis.

Circadian entrainment of metabolism

Warning!, sloppy and controversial post incoming!


My interest in the 23/1 intermittent fasting regime was piqued again recently after reading this link. Its about Ori Hofmekler's Warrior Diet, I read this book in the day, and although I did agree with it, the science has since come along more to support his ideas over the years. However I believe I can take his theory further and really get to the "liver" of the matter. I propose that Ori's theory is correct only in as so much as your circadian rhythm is aligned with the light/dark cycle.

If you maintain a circadian rhythm such that you sleep during the day and are awake at night, you should still be able to reap all the benefits of this 23/1, because the key point about the whole thing is really to fast during the hours following waking up, while your liver AMPK activity is high, and your liver is burning fat like crazy. Then, 9 hours or so after waking, when diurnal cortisol flatlines, liver AMPK activity starts to fall off, liver fatty acid oxidation slows, and this flips the switch that turns on hunger. You now have an approximately 4 hour window to get in your big daily meal. I say 4 hours instead of 8 hours because I dont advise eating a massive meal just before going to sleep.

Now I want to get more into the "liver" of the matter why Intermittent Fasting in general is oh so important .

First some important things to recall, hepatic fatty acid oxidation controls appetite. When hepatic fatty acid oxidation falls, hunger increases. I firmly believe that is NOT just a coincidence, but is actually part of the circadian rhythmic tone of food intake.

If you've been reading Peter's "Proton" series recently, you should know that fatty acid oxidation induces insulin resistance. High levels of fatty acid oxidation in the liver likely contribute to making it IR, especially upon first waking in the morning.

Next, the degree of PPARα activation in the liver is positively correlated with liver fatty acid oxidation. ( The paper in that post also suggests that PPARα activation may have the power to reverse fatty liver btw. )

I also went back to read the full text of this paper Lets ignore all the bullshit about high-fat-diet VS chow. I only want to look at the Ad Lib feeding vs IF aspect. The important graph from this paper imo, is this one....

Red line = IF mice, pink line = Ad Lib mice.

PPARα is a surrogate for liver fatty acid oxidation, we can safely say then that liver fat oxidation was substantially higher in the IF group. From the graph above we see that, after feeding in the IF group , PPARα shoots up then gradually declines until a few hours before feeding again. This essentially means that, all that time PPARα was elevated, hepatic fatty acid oxidation was increased and hunger was most likely diminished.

The decline in liver fatty acid oxidation before feeding is also important, because this would naturally make the liver more insulin sensitive. Exactly what we need before we cram food down our throats.

Fatty acid synthesis inhibits mitochondrial beta-oxidation. This right here, is the breaking of the CICO theory.

Malonyl-CoA, a product of ACC activity in the first step of fatty acid synthesis, allosterically inhibits mitochondrial carnitine palmitoyltransferase (CPT). CPT is essential for the transit of longchain fatty acids and acylcarnitine esters into the mitochondria for b-oxidation. Increased hepatic malonylcarnitine levels in FA mice, but not in FT mice (Figure S4B), are indicative of the specific disruption of fatty acid oxidation caused by impaired entry of fatty acids into the mitochondria.

And this.....

increased levels of the transcriptional repressor Rev-erba (Figure 2E) led to reduced expression of its direct target and a key lipogenic gene, fatty acid synthase

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Food intake and insulin stimulate fatty acid synthase. ( 1 ) , this blocks liver fat oxidation which in turn stimulates appetite. In order to overcome that increase in appetite, you need incretins from the food you just ate. The satiating affect from the incretins you get must be enough to offset the hunger stimulated by the drop in liver fat oxidation. This is a good reason why eating big and rarely wins, while eating small but often FAILS.

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So what controls the diurnal pattern of Liver AMPK and fatty acid oxidation in liver? I think theres a chance its ghrelin. ( 2 ) . As meal time approach's, the circadian clock of the gastric system starts secreting ghrelin more.  This has the affect of reducing liver fat oxidation, stimulating hunger, and allowing the liver to become more insulin sensitive in preparation for the feeding. ( 3 ) 

It should be apparent by now that circadian entrainment of food intake is as vital as circadian entrainment of sleep. If I told you I didnt sleep straight 8 hours every night, but instead slept in 3 small bursts of 3 hours, would you think that was healthy? How good do you feel when you get a solid 9 hours of deep sleep. Compared to continuously waking up in the night and lying awake for 1-2 hours before returning to sleep.

The discontinuous sleep makes you feel like shit doesnt it?

So why is it then, when it comes to food, which is also dependent on circadian rhythmic  
 tone, that we insist on getting our calories in 3 small short bursts? i.e. breakfast, lunch,dinner? If getting our sleep in one large burst is healthy and makes us feel good, why wouldn't getting our daily calories all in one burst also be healthy? I.e. 23/1 Intermittent fasting. 

( BTW yes I know the mice in the intermittent fasting study weren't doing 23/1, they were doing 16/8 , but as far as im concerned, the fact remains, eating at the SAME TIME everyday is as important as sleeping at the same time everyday. And dont randomly nibble on food, youll fuck up your circadian clock of ghrelin secretion leading to random hunger pangs, like randomly napping during the day can affect your sleep at night. Random nibbles also risks inhibition of liver fat oxidation while failing to generate necessary incretin secretion to keep you un-hungry, )

High Leptin in fat people

OK, its well known fat people have high leptin. But why? Is it because of leptin resistance in the brain, as most people seem to think? OR, is it because of something else? Most scientific papers simply state that "leptin circulates in direct proportion to fat mass", subtly implying that fat mass determines leptin secretion.

hhhhhmmmmm, im suspicious that there is more too it...

Apparently some people are still under the impression that insulin doesnt make you fat. Thats only partially correct, it is insulin sensitivity of fat cells that determines the fattening power of insulin. Having a ton of insulin will indeed not make you fat if there's no insulin receptors on the fat cells. One of the first things discovered about leptin was that its secretion was enhanced dramatically in the presence of insulin. I.E. insulin signalling in fat cells produces leptin.

So, do fat people have high leptin because they generally also have high insulin? Maybe.

But how does insulin cause leptin secretion anyway? Whats the mechanism? Well, one of the things we know that insulin does is promote glucose uptake through increased GLUT4 on the fat cell surface. Right, so is increased glucose uptake responsible for leptin secretion?

Maybe.

Once glucose gets into the adipocyte, there are several fates for it. It can either be converted to lactate and exported, it can be oxidized, or it can enter the lipogenesis pathway. Obviously going down the lipogenesis pathway is not something you want if your trying to stay slim. Im not sure exactly what determines which path the glucose takes, but astonishingly, Metformin enhances glucose uptake into fat cells. ( 1, 2 )

Remember that metformin is much more strongly associated with weight loss, and from these papers we learn that although metformin causes glucose uptake via GLUT4 expression, the pathway for this glucose is lactate production and oxidation, which helps explain why metformin doesn't make you fat, but actually quite the opposite.

In that first paper, the researchers speculated that glucose going down the lipogenesis pathway in adipocytes might be the signal for leptin secretion, and these musings would be confirmed a few years later by a further study that shows glucose incorporation into lipid, at least during insulin-stimulated conditions, leads to leptin secretion. ( 3 )

So we are left with the reasonably strong conclusion that Lipogenesis causes leptin secretion. The corollary to this is that the amount of leptin found floating around in the blood is a direct indication of the amount lipogenesis from carbohydrate going on in your fat cells. This, in turn, I would propose, is a direct indication to the insulin sensitivity of your fat cells.

The fact that lipogenesis is the stimulation for leptin secretion should not really be all that surprising, one of the primary jobs of leptin is actually to stimulate lipolysis via the nervous system once its found its binding sites in the brain. Using a crude example, adipocyte takes in 1 triglyceride, in return, 1 molecule of leptin is secreted, it floats around the blood eventually arriving at the brain, where it lets the brain know we have 1 triglyceride in storage ready for energy usage in the future. The brain can then order the mobilization of that triglyceride via the nervous system by stimulation of lipolysis in the adipocyte, thus creating a perfect negative feedback loop system where system stability is maintained.

Summary : The high levels of leptin found in fat people is very likely an indication of elevated insulin sensitivity and lipogenesis in their fat cells.

Niacin to beat infections?

Another new study which caught the attention of the media is about how niacin ( nicotinamide ) has the potential to boost the bodies white blood cells when taken in large doses ( large doses meaning 2g+ per day ), this boost in immune response allows you to better fight off virus and bacteria infections.

C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

I first saw it reported here ( I would invite people to read this and the comments for themselves )

Apparently you can even kill deadly MRSA with high dose niacin! No need to spend hours in freezing cold water AKA Jack Kruse.

Nicotinamide is the version of niacin that I kind of dont like because it doesnt cause the skin flushing affect, personally I would stick with nicotinic acid, the flushing variety. REMEMBER the secret to niacin is to take it away from food and to fast for 5-6 hours after because it makes your serum FFA spike which in turns make you severely glucose intolerant and insulin resistant.