Thursday, August 23, 2012

Protons: de novo lipogenesis

Okay, time to think about whole body insulin sensitivity, adipocytes and insulin.

First the core process; adipocytes which are listening to insulin will post GLUT4s on their surface, accept glucose and do enough de novo lipogenesis to both store and release palmitoleate. The palmitoleate is a signal that there is plenty of glucose around, let's use it.

Adipocytes are accepting glucose for signalling purposes and DNL lipid formation, plus they are sequestering away whatever lipid is available from the diet. The core function of insulin is the storage of DIETARY fat under the influence of carbohydrate. Boy, that is an old post! But the fact that there is plenty of glucose around means that the body should maintain insulin sensitivity, to make use of that glucose. But DNL in adipocytes which are insulin sensitive makes you, err, fat. As Cao et al point out in their lipokine paper:


"Additionally, genetic or pharmacological manipulations that boost de novo lipogenesis in adipose tissue (even though this sometimes leads to expansion of the fat depot) are associated with improved metabolic homeostasis (Kuriyama et al., 2005; Waki et al., 2007)."


I think this is a long winded paraphrase of the Hyperlipid concept "Getting fat is bad when you stop".


Increased insulin sensitivity in adipocytes makes you fat. That's as you would expect.

Back to the ice pick rats with their acute onset insulin hypersensitivity in adipocytes. During rapidly increasing bodyweight (on a low fat diet) there is a marked increase in obesity with excellent insulin sensitivity. Ended by six weeks.

Ditto MSG rats, but for in 4 weeks rather than 6 weeks. Can't tell from the gold thioglucose abstract, but at least a few weeks. Probably depends on all sorts of minutiae.

While ever these rodent models are gaining weight they maintain insulin sensitivity because they are doing DNL to get fat. On a low fat diet increasing obesity means DNL, palmitoleate and the ability to run metabolism on glucose. Logical.

Only once a brain-damaged rat becomes obese enough does hyperinsulinaemia set in, with attendant glucose intolerance. By this stage adipocytes are insulin resistant so have reduced ability to respond to insulin, reduced GLUT4 expression and, presumably, reduced palmitoleate synthesis. From the adipocyte's point of view there is not a lot of insulin around, whatever the blood concentration might be.

Lets look at the converse to obesity:

What does a lack of insulin signify? No food (or no carbohydrate, pax protein). Starvation requires insulin resistance as an obligate state for survival. How much good is palmitoleate going to do you under starvation or ketogenic dieting? Not a lot, unless you enjoy dropping precious glucose in to muscles until you brain falls to pieces.

An adipocyte which sees no insulin will not generate palmitoleate. If it generates anything at all (doubtful) it will be palmitate. Releasing some residual palmitoleate from adipocytes is fine for a few days, as long as there is glycogen hanging around. By three days this will be gone and so too should the palmitoleate. You are now in to hard core survival driven insulin resistance.

That's where I live.

Adipocyte distension induced insulin resistance is completely different. Here the adipocytes see low insulin when there is a ton of it around. There is a ton of glucose around too. But an adipocyte acts as per starvation and does what would be absolutely the correct thing under starvation circumstances. It releases palmitic acid and stops generating palmitoleate. Doing this while the macroscopic organism is eating bagels and french fries is bad. It's bound to generate massive hyperinsulinaemia to normalise glucose in the face of a ton of palmitic acid.



I'm just wondering whether there is time to look at the C57BL/6 mice. Just briefly as there is a lot of Mickey to be extracted on this subject when we get to idiots in detail. Briefly:

By an utter quirk of metabolism the VMH of C57BL/6 mice breaks under high dietary fat levels. So they have access to ample dietary fat when their VMH is injured, by definition. They store this fat because sympathetic tone to adipocytes is acutely lost and adipocytes become exquisitely insulin sensitive. Fat falls in to adipocytes as soon as the injury occurs, probably within hours of eating some butter, almost any amount of butter, however small.

But the fat they store is dietary fat. No DNL. They do not need to gain fat by DNL as it is there in the hopper. Dietary fat falls in to adipocytes. Palmitoleate synthesis? When fat is distending adipocytes so fast they are leaking FFAs despite losing lipolytic sympathetic tone? There is a ton of dietary fat dropping in to adipocytes, this is what gets released as they distend. By day three C57BL/6 mice are systemically insulin resistant. Their palmitoleate levels will be low and palmitic acid levels high. They are just a modification of the ice-pick/MSG/gold thioglucose family, but the process happens at warp speed due to the availability of DNL-free bulk fat.

Even on high fat plus high sucrose diets humans do not injure their VMH, at least not immediately. But C57BL/6 mice do and they have taught me a great deal over the years, made me think a great deal too. But they are still just a model, as explicable as the rest of the models, from the insulocentric point of view.

Once you have enough data.

To summarise: Palmitoleate is released by adipocytes when glucose and insulin are plentiful. Palmitate is released when glucose is sparse and insulin is low.

The sh!t hits the fan when glucose and insulin are plentiful but adipocytes are so distended that they THINK glucose and insulin are low. When both insulin and glucose are high you want palmitoleate. If your adipocytes give you palmitate under these circumstances you had better have a pancreas of steel or diabetes here you come.


I think we might go to PUFA and SCD1 in adipocytes before hepatic DNL in this series.


BTW It's nice to see people in comments being a post or two ahead! At least this isn't complete gobbledegook to everyone!

Peter

13 comments:

Kindke said...

Spanner in the works time!

Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

Theres 2 angles to this paper, if you over-express GLUT4 in adipocytes you get increased glucose uptake and obesity.

But if you over-express glucokinase in adipocytes you get increased glucose uptake but stay lean. lol wha? The basic idea seems to be that the rate of glyceroneogenesis in adipocytes determines how fat you get.

BTW peter this post was very clear and explains alot :)

Jack Kruse said...

Peter another home run. You are laying the pathways out and I hope you keep headed to the main target in the brain. Palmitic acid effects on the hypothalamus on insulin and leptin receptor. Soon I hope you will be discussing dietary palmitic acid production vs pathway induced palmitic acid (DNL from carbs n PUFU'a).Dietary palmitic acid causes a temporary "leptin resistance" as long as it is not chronic. Moreover, it appears what really causes obesity is the chronic inflammation from system DNL increasing massive amounts of palmitic acid leading to a chronic leptin resistance. The nuance of this all is replacing palmitic acid containing saturated fats with dietary carbohydrates. This is converted to palmitic acid by DNL in the insulin resistant person with an no room left in their adipocytes! It can also occur with many polyunsaturated fats which also drives the inflammatory cascade in the brain to wire it into the system. It is classic Hebbian learning. Eventually it appears you will arrive at the leptin receptor and its out flow tracts. What happens at the hypocretin neurons (orexins) are critical. I am looking forward to this as you lay all the framework.

Nostril Damus said...

Thanks Peter! This great post is a bit more digestible to a non propeller head like me than some of your other recent gobbledegook.

I believe Rosedale has also long beaten the flabby you-are-lucky-if-you-get-fatter-coz-it-protects-you-from-diabetes drum.

George Henderson said...

Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice
http://www.ncbi.nlm.nih.gov/pubmed/22768070

"The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16∶1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression.

Compared with controls, palmitoleate supplementation increased the circulating levels of palmitoleate and improved systemic insulin sensitivity. Locally, hepatic fat deposition and SREBP1c and FAS expression were significantly increased in palmitoleate-supplemented mice. These pro-lipogenic events were accompanied by improvement of liver insulin signaling. In addition, palmitoleate supplementation reduced the numbers of macrophages/Kupffer cells in livers of the treated mice.

Together, these results suggest that palmitoleate acts through dissociating liver inflammatory response from hepatic steatosis to play a unique role in NAFLD."

So,even for the liver, getting fat is (only) bad when you stop...

George Henderson said...

P.S.
I really enjoyed this book, which tackles all our favourite topics and authors in a funny way with some good social observation of diet in 60s and 70s Britain:
http://www.dailymail.co.uk/femail/article-2105132/Damn-low-fat-diet-How-reformed-vegan-John-Nicholson-gorges-foods-granny-enjoyed--felt-better.html

Eva said...

OK, yeah that was easier to follow! Just need a few simple version paragraphs once in a while to make a basic frame work. Then the more complex stuff can be more easily fit into its place bit by bit.

I am hoping down the line, some suggestions/ideas/concepts will be generated on solutions beyond the usual eat more meat, less carb, avoid wheat, etc. If problem resides in central nervous system, might be issues with excitotoxins, msg, etc also having contributed. Anyway, I'd like to see some day some added ideas for those for whom the basic as we currently understand them paleo interventions haven't fully worked. Not everyone gets fully metabolically 'fixed' by paleo. The standard theme seems to be that if paleo doesn't work, then tough cookies you are broken. I am not ready to accept that yet. Given the right conditions, humans have wonderful healing powers. I'd like to see more effort into understanding the mechanisms better and coming up with additional potential interventions and/or dietary tweaks. That's why I read this blog even when I don't understand every molecule of it.

Intervention/prevention is wonderful but what with current institutionalized bad advice by 'experts' on all levels, there will be few that figure it out before at least some level of potential damage has set in. Almost everyone will be needing fixing, very few will have prevented. Let's hope blogs like this can help pave the way for future solutions. -Eva

Jack Kruse said...

Peter I hope you delve into TXNIP too at some point in this series. TXNIP is pure hypothalamic protein that is heavily influenced by leptin and overall energy status. When hypothalamic expressing neurons secrete TXNIP is completely alters the calorie in and calorie out dogma that exists today in science and promulgated by many obesity researchers, and completely fits in alignment with what I have believed for many years now. The brain has a way to calculate overall energy status and it can regulate consumption and metabolic efficiency in a different manner than we currently perceive. Humans wrongly believe the best way to lose weight is stop eating and control calories. This is wrong. The best way to modulate the system is affect the metabolic pathway inefficiencies. This is the best use of TXNIP to do this.

The major plays are BG, insulin and leptin status. Interestingly enough the latest research is beginning to show it is not a shared thermostat with all three players getting equal footing. It appears leptin is the major player and this make tremendous sense because insulin is a small player in colder temperatures but huge in warmer temps. The lower energy expenditure in hTXNIP-expressing neurons means we get fatter because metabolism is slowed down centrally. The interesting part of TXNIP is that is also shows why body builders were ahead of the game and why IFing really works at the brain level. Insulin spikes from any source will also alter TXNIP to induce lipolysis. This was going to be the focus of my Low carb cruise talk. I was going to explain to the low carbers on the cruise that all you believe has to be challenged by the new science as it is revealed.

I dont believe all carbs are bad as Rosedale does. I believe in biologic and evolutionary context. Not all carbs are bad…….when they are eaten at the correct times of the year. Summer time carbs when it is warm can actually lean us out and the science of TXNIP is the proof of that concept. What the CT protocol does to TXNIP is interesting. It lowers it tremendously via the effect on leptin and BG. This is why CT is massive help to obesity and to FBG. Most people do not even realize this science exists and it appears to me based upon this current series you do by laying foundational pathways.

O Numnos said...

Ok, I'm going to stick my simpleton headed neck out here inspired Dr Kruse's last post.

In my n=1 experience and experimentation both accidental and purposeful, I am coming to the opinion that in (non-broken) people, the body uses Nitrogen balance as a proxy for energy availability independently of dietary energy intake - as long as there is some ar!e lard to make up the shortfall.

You could make a case (albeit simple) that this makes some sort of evolutionary sense.

Peter said...

Kindke, it looks like the cells accept glucose through an increased concentration gradient due to increased phosphorylation. Almost non of it gets in to mitochondria, presumably as insulin controls pyruvate dehydrogenase. Lactate is the output at F:N of 0.2. But generally the paper bends my head and I have too many other threads to tie together at the moment! Why it's differernt to fructose is an interesting question. If it is different...

Jack, I don't know if I'll ever get even remotely near your knowledge of the CNS neuronal circuits. I'm just picking at the basic processes which the brain fine tunes. And how cells live or die under various energy states. It's very gratifying to see the recurrent convergence of ideas. SCD1 and peroxisomes post is sketched out but of course sitting in a cold pool probably does the same thing, but without the SCD1 gene deletion being needed! I think we are coming at the same basic physiology from radically different directions. But the convergence is certainly there...

Nostril Damus, phew, good.

Eva, not everyone wants to be fixed. You have to drop out of the paradigm before you can become disillusioned with the poor results of paleo (or LC). I get almost no time to read around the net, I keep an eye open for a few bloggers, but I really don't have much of an idea of what goes through the paleo or LC fora. I'm really fascinated by the physiology, what goes wrong and what goes right... The guy on the potato only diet speaks to me in terms of NADH only. Does anyone know if the diet is universally applicable? I can see some logic if you don't mind using glucose plus insulin sensitivity to control weight. Sounds catastrophic on any other front to me. No one made an animal model extend its longevity by adding sugar to its diet (though I have vague memories that it has been done, possibly in research cited by Ray Peat, dunno)...


George, ah, there is some exchange in comments with Jane re iron. Hepatic lipid overload and iron retention is a potentially rewarding idea. Copper too. Got to get that superoxide from somewhere. My wife gave me a throw away tidbit that all pathologists just "know" that cirrhosis is associated with copper, as well as iron, overload. Hmmmmmmmmmm...

O Numnos, perhaps but protein restriction, especially sulphur amino acids, appears to prevent metabolic syndrome. There seems to be more to it than that we eat to 0.7g/kg/d of high quality protein. Though this might actually be ideal... That's a whole new ball game!

Peter

Jack Kruse said...

Peter your are far too modest. The biochemistry you are laying out is foundational from an evolutionary standpoint. You are correct that I am coming to this problem from another avenue but rest assured the path you are on is going to lead you right into my Brain Gut 5 post for human human evolution. This pose on DNL is critical. The next step is delving into mTORC1. This pathway promotes de novo lipogenesis through the activation of SREBP-1. Many, like Rosedale are found of blaming mTor for early death but nothing could be further from the truth. After oncogenesis occurs the molecular machinery of FAS and mTOr is usurped by cancer and used for its own devices. This is why so many people think mTOr is bad for life when in reality the reverse is true. We need excellent mTOr function for longevity. The genetic changes in cancer progression are a not a cause of cancer production they are the RESULT of it. This relationship has been so misunderstood by cancer researchers and clinicians this is why they continue to flounder. The key is the loss of normal molecular signaling of these pathways. The effect of inflammation on DNL is one of those key pathways that show what happens. You are laying it out. On my end, here is what happens in the brain when the cellular biochemistry is destroyed. All cancers that activate DNL destroy the cortisol/DHEA/melatonin axis in the brain's HPA and the key result is finding low brain melatonin. Melatonin is the third most important antioxidant in the brain, but most important at night. The Key to DNL is understanding that it destroys the nighttime circadian signals of leptin entering the brain at midnight and then signaling the prolactin surge. This prolactin surge is tied to brain dopamine levels. if they are good things are fine. Normal circadian signaling then proceeds to release the Growth hormone in pulsatile fashion form 2AM to 5 Am. When this is normal is signals the slow steady rise of cortisol from 5AM to 7AM that peaks when we awaken to turn on the lights in the brain. When it fails cortisol is low in the AM. When this happens it signifies the patient has a major issue with DNL. This means T2D most frequently clinically. When GH is low, melatonin is low, cortisol is low in the AM and the result is obstructive sleep apnea which riuns body comp and further lowers body and brain melatonin levels. When this is chronic.......we get cancers of epithelial tissues. Breast, thyroid, pancreas, uterus, ovary, skin, etc.......this is why it happens. This is why T2 D is associate with bad sleep, OSA, low IGF1 poor body comp, and epithelial cancers. This is the giant circle of life. Your post here is the micro of the issue at a 30 ft level and I just gave my view from the clinical point. You my friend are a rock star. Keep it up. You will slay the dragons that we have to deal with over here in the USA paleo-land. They just don't get it and you clearly do. It is a pleasure to ready your work. It is is complex and fascinating but with any puzzle the best way to solve it is to change your perspective of what you believe to be true and come at it a new way.......you and I our like steroisomers coming at the problem two ways but we surely will meet someday if you continue this journey you are on. The world needs this work more than you might even appreciate.

Jane said...

Peter, does your wife mean Indian childhood cirrhosis? It was found to be associated with excess copper due to the use of brass utensils. But a second factor was apparently needed, and actually copper isn't really hepatotoxic.

'.. Cases of liver disease in adults attributable to excess copper ingestion are rare. A 58-y-old psychiatric patient who ingested 275 American coins, which were largely made of copper, died from profound hemolysis. However, postmortem examination revealed no cirrhosis (52). ..there is no direct evidence in humans or in other mammals that newborns are more susceptible than are adults to hepatic damage from copper ingestion. ..'
'Role of copper in Indian childhood cirrhosis'
http://www.ajcn.org/content/67/5/1074S.full.pdf

Peter said...

Jane, no. If you take any cirrhotic liver it will have copper accumulation, as well as iron. It makes it a bugger to diagnose Wilson's disease on advanced cirrhotic livers. Just because your liver is copper positive does not mean you have a copper storage disease or have copper excess ingestion.

At least one internal medic at the RVC has a fetish for getting livers stained for copper. We clinicians all have our foibles... Pisses the pathologists off somewhat. The special stain for copper ia complex and takes hours to (normally) get a negative.

Peter

Jane said...

Any cirrhotic liver has copper accumulation? That's interesting. I wonder why that should be. You'd have thought the iron accumulation was due to copper deficiency. Perhaps the problem is that the copper can't get out, either to the bile for excretion, or to the blood to enable iron export.