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Welcome all seeking refuge from low carb dogma!

Thursday, July 15, 2010

Nutrient Fates after Absorption

After a meal, the metabolic fuel selection at the whole-body level depends on the plasma concentrations of nutrients such as glucose, non-esterified fatty acids (NEFA) , amino acids, and on hormonal responses. Over the last 10 years, there has been great interest in studying the metabolic effects following the ingestion or the intravenous (i.v.) infusion of the three macronutrients, carbohydrate (CHO), fat, and protein (or amino acids for i.v. infusion). The aim of the present brief review  {I'm thinking it's not so brief!}  is to summarize the main mechanisms which determine the post-absorptive interactions between the nutrients.
This is an older paper, but still recent enough to provide some good info on the basics.  I'm going to do something a bit different with this one and I otherwise would be quoting huge chunks.  So I'll do bullet point summaries with select summary quotes from the paper in italics.



Carbohydrates:
  • Four fates:  Oxidation, Storage as Glycogen, Triglyceride synthesis (TAG, de novo lipogenesis) or conversion to gluconeogenetic precursors.
"It is to be emphasized that other metabolic pathways for disposal of dietary CHO, such as conversion into TAG or into non-essential amino acids, are not quantitatively important."
  • Our extracellular capacity for glucose (e.g. circulating) is only about 10g so most dietary glucose that cannot be immediately oxidized is converted to glycogen to store for future use.  
  • Upon ingestion of 100g glucose, about 40g is oxidized, 50g stored as glycogen and 10g not yet absorbed in 3 hours.  Fuel partitioning for energy in that period is 60% from glucose, 25% lipid oxidation and 15% protein oxidation.
  • Normal glycogen stores are between 250 - 500g, on the order of magnitude of "normal" carb consumption of 250-300g/day 
  • Several studies are listed indicating that excessive carbohydrate ingestion is accommodated for by increasing carbohydrate oxidation and glycogen synthesis.  Minor lipids formed by DNL were subsequently oxidized.  
"The important point is that there was no gain of fat by de novo lipogenesis, as a small amount of net lipid oxidation was observed."
  • Chronic overeating of carbs results in an increase of glycogen stores by about 500g before DNL becomes significant.  Only with chronic overfeeding and saturated glycogen stores does conversion of carbs to fat become significant.
"de novo lipogenesis is not an important pathway in humans"
Carbohydrates do not contribute to "fat accumulation" by excess carbs being converted to fat.

Dietary Fats
  • This consolidated section generally confirms my understanding of adipose tissue as a transient regulator of NEFA levels.  
  • Most dietary fat transported in chylomicrons is taken up by fat tissue.  Insulin does suppress NEFA release, but never entirely.
"It is to be emphasized that adipose tissue LPL activity does not necessarily imply net storage of lipid; from 180 to 300 min after a meal adipose tissue is able to convert circulating TAG into NEFA, not storing the majority of the fatty acids derived from circulating TAG. Human adipose tissue is not simply a reservoir for food energy, but it is an important tissue for the disposal of circulating TAG postprandially."
"It can be concluded that within a reasonable range of CHO-energy : fat energy, the addition of fat to a meal does not substantially increase fat oxidation."

Glucose / Fatty Acid Competition

  • There is evidence of competition between glucose and FA's as oxidative substrates, the exact mechanism is not known but the Randle hypothesis is not applicable to humans.
  • Increases in NEFA correlate with reductions in insulin-mediated glucose oxidation
  • Elevated NEFA plays a role in the development of insulin resistance

Interactions of the Three Macronutrients ~ I.V. Infusion Experiments

Amino Acids:
  • AA's increase gluconeogenesis rate and glucose production in the liver along with a slight rise in glucose oxidation.
  • AA's stimulate insulin and therefore increase glucose clearance. 
  • AA's do not inhibit glucose oxidation in contrast to FA's
Fatty Acids:
  • Lipid infusions do not stimulate glucose production in the liver but do increase gluconeogenesis.  I find this confusing because I assume GNG produces ... well ... glucose.  Or perhaps glycerogenesis takes the glucose --> glycogen?
  • NEFA/FFA infusions are to be interpreted with caution anyway with regard to dietary nutrients.  Circulating dietary fats are mostly as chylomicrons.
FA's + AA's:
  • Simultaneous infusion led to increased gluconeogenesis and peripheral insulin resistance, but this is offset by insulin release when fed to normal individuals.
Post-absorptive Protein:
  • Nitrogen balance is fairly tightly controlled
  • Ingested protein stimulates protein synthesis and turnover
  • Increased energy expenditure (TEF of protein) is accounted for by the metabolic "cost" of protein synthesis.
Ethanol Surprise!:
  • Ethanol in a meal suppresses lipid oxidation (no surprise there)
  • Ethanol has about a 20% TEF!!  

"N balance is achieved on high or low (but sufficient to meet requirements) protein intakes; similarly, CHO balance is also precisely regulated since the glycogen stores are stable from day-to-day, and de novo lipogenesis from CHO is not an important pathway in humans. Thus, both protein and CHO intakes promote their own oxidation, and the 24 h intake of these nutrients determines the respective amounts oxidized. By contrast, fat intake does not promote its own oxidation, and fat balance is not regulated by oxidative metabolism. Fat balance mainly reflects changes in energy balance. The regulation of fat balance is, therefore, much less precise than those of protein and CHO.  This is to be expected because large daily errors in fat balance involve amounts which are very small in comparison with the body’s fat reserves (Flatt, 1987). In addition, errors in fat balance do not elicit appropriate responses in food (and fat) intakes that could ensure the maintenance of fat reserves (Blundell et al. 1993)."

This article goes a long way to explain why the "Standard American Diet" or "Western Diet" is fattening.  Metabolic signalling is tightly controlled for carbs and proteins, but if one eats 100g fat or 200g fat in the context of their diet, this is roughly 1/4 - 1/2 lb, and represents a tiny percent of total fat stores even for a lean person.  

20 comments:

gn said...

so, what's the take home message in terms of ad libitum eating: one can eat as much of carbs and protein as they like if fat is low, or high fat if everything else (especially carbs) are low?

CarbSane said...

I guess the thing is how you define "as much as you like". If you're not REALLY in tune with your hunger signals (see my musings on When to Eat for instance) ad libitum can lead to overeating regardless of diet composition.

But it does seem that our physio signaling is far more attuned to carb and protein intake (because dietary amounts can at least theoretically rival storage capacity) than fat intake that cannot even come close to storage capacity even for a very lean person.

Epidemiologic data point towards high carb low fat diets leading to low obesity rates and longevity. We can't ignore this. And yet, humans are highly adaptable, and high fat low carb diets certainly lead to weight loss in most, and seemingly have no ill effect (and may be beneficial) in cultures like the Inuit. Still, there seem to be far more examples of the former, and most VLC/VHF diets nowadays differ radically from the Inuit diet.

What this paper did summarize is that the primary fate of dietary carb and protein is not fat storage.

Welcome gn!! Thanks for reading and your comments :)

gn said...

so, as far as my unsophisticated in terms of formal biochemical education mind understands, the more carbs and protein you eat, the faster you burn them (upregulation of metabolic rate), and, 'fat-wise', you preferentially burn those two; in comparison, fat is somewhat a 'long-term' nutrient, and is designed to be stored first and burned later if nothing else is available - i wonder what would be the evolutionary rationale for such an architecture?: i mean, from what i've been reading re 'paleo', we ate primarily fat, with carbs being rather scarce, so we were storing them asap (as fat) in anticipation of lean days, but here we store fat and burn carbs - i should say that to accept this notion one should have a sort of a paradigm shift...

on a practical (ad-libitum) side: suppose one's daily caloric requirements are 3000 c., but ad-libitum a person wants to consume 6000, and it happens that those 6000 would be in form of a cake: flour/sugar (carbs) + eggs (protein) + butter (fat); regardless of taste, what would be the best proportion of each of the components in terms of minimizing subsequent DNL and upregulating BMR?

CarbSane said...

Yes, this is part of the thermal effects of food (TEF's) which are highest for protein (>20%) -- don't quote me on the exact numbers here -- carbs (8%) and fats (3%). It is important to recognize that these changes are transient and may or may not have any significant impact on total daily energy expenditure (TDEE).

The evolutionary advantage of such a structure is fairly simple in my mind. The same amount of energy stored as fat vs. glycogen & associated water is high, so carb storage is limited so that we can move from place to place carrying less weight.

The other reason is pure chemistry/physics. Fats and water don't mix. It would be of evolutionary benefit to be able to eat large amounts of fat when available and be able to clear them from the bloodstream rapidly.

We use free fatty acids for energy, the level of which to be used for fuel is closely regulated hormonally by release from adipose tissue. For example in "fight or flight" adrenaline will cause an acute release of NEFA from stores. The triglyceride form is the storage form and the form from dietary fats (e.g. chylomicrons) that are also distinguished by the body from repackaged/synthesized fats from the liver (e.g. VLDL).

If you click on my NEFA/FFA topic, I have spent a lot of time researching this. Elevated NEFA are associated with dysfunctioning fat, insulin resistance, and diabetes.

I won't even speculate over what a 3000c excess should consist of macronutrient-wise. Whether or not primitive man gorged himself when he had the opportunity, it is reasonable to assume such sessions were followed by fasting periods or at least food scarcity. In the modern world, where food is plentiful and we have to expend very little energy to procure it, significant energy excess is not advised at any time. That said, my pseudobulimic days (if we define bulimic strictly as instant purging by vomiting and/or laxative abuse, I attach pseudo for most of my bulimia which was alternating binge/fast phases) do not seem to have resulted in any lasting damage to my health, although they consumed the bulk of my "formative" years. But I wouldn't recommend this eating behavior to anyone!!

Sanjeev said...

I tried to post this before but it didn't go through - maybe it will this time

my theory on fat vs carbohydrate burning:
take the hypothetical case of a race between a man who burns fat first & man who burns carobhydrate first.

The carb burner, in addition to the CO2 and h2O from combustion, will also release several grams of water for each gram of glycogen burned.

The fat burner will have to carry the glycogen plus the hydrating water for the whole run.

Over a 1 hour or longer run this will be a significant disadvantage for the fat burner, meaning, there's an evolutionary advantage to getting rid of your carbohydrate (and getting a small hydration benefit) at the start.

CarbSane said...

Interesting theory there. Makes sense to me, and it's not something I've thought of or heard before.

I would add to this my speculation that it isn't even NEFA liberated from our adipose tissue that are burnt for fuel (at least initially), but rather that lipids pre-existing within the cells (called intramyocellular lipid or triglycerides) are oxidized, and the NEFA's flowing into cells replenish the stores. There would be a slight lag for the IMCT to be hydrolyzed and transported to the mitochondria. This speculation is based on the fact that trained athletes have higher levels of IMCT. I'm not sure how this could be demonstrated?

Welcome to my blog Sanjeev, thanks for reading and commenting!

Margaret said...

Just recently discovered your blog - very well done and informative. I am enjoying all the debates. I have a big question though - why do you say the Randle cycle is not applicable to humans? I have been reading an excellent review by Keith Frayn on this topic (Biochem Soc Trans 2003;31(6):1115-1119) that describes the Randle cycle and its role in mammalian metabolism. Thank you for any comments you might have in response.

CarbSane said...
This comment has been removed by the author.
CarbSane said...

Hi Margaret! Welcome and thanks! I think Jequier makes this statement based on the simple model of Randle. In humans, and "higher beings", blood glucose levels rarely fall much below normal. In Newsholme & Start this is one of the factors they consider in describing the triglyceride-fatty acid cycle so that that cycle must depend on something other than the simplistic 2-way competition/feedback of Randle. Here's a link for the rest of you to the paper Margaret is talking about by my "sci-crush" Keith Frayn: The glucose–fatty acid cycle: a physiological perspective

I'm not sure I ever posted this on the blog. Gonna go make one of those "bookmarking posts" now! Thanks :-)

Margaret said...

Thanks for the response and for the bookmarking post. I have just splashed out and ordered "Metabolic Regulation - A Human Perspective" by said K. Frayn - the 2010 edition. I got my biochemistry degree back in 1979 and all these new theories and research are making my head hurt - I need to review all the basics! I figured Frayn was the best way to go!

CarbSane said...

I think you'll like the book if it's written anything like the edition I have. Not a bad read at all. Newsholme was quite a bit more a challenge in parts but one of these days I'll tackle some of the other chapters in there not mangled in GCBC ;)

Craig in CT said...

Some in the low carb/paleo community clearly believe that you can't possibly get fat by eating fat. This never made a lot of sense to me from an evolutionary perspective. The ability to store excess calories as fat is clearly an advantage with respect to surviving periods of famine and unsuccessful hunts. If paleo humans did get a substantial proportion of their calories from fat (dead animals), then it would make sense that this would be what they would be able to store. If carbs were so rare in the diet, why would they be highly evolved to store energy from carbs, but not from fat.

Thomas T said...

Hi C.S!

Whilst I have previously been a believer of the "de novo lipogenesis as the road less travelled", I have been reading some more research into the topic. With different technology/techniques for analysing DNL, it appears that some scientists still have not done the about-turn, and are claiming that DNL can be significant even in a balanced caloric state (i.e. not massive overfeeding) when fat is relatively low and carbs are high. What are you thoughts? Here is one of the studies I am referring to:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC507283/

Evelyn aka CarbSane said...

Interesting Thomas -- in Hellerstein's later work (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC408572/pdf/JCI9906572.pdf) DNL didn't seem to contribute much to the VLDL triglycerides. Most do seem to put the caveat "in the context of a Western diet" when talking about the contribution of DNL. A liquid 75% glucose polymer diet seems rather extreme. Anyway, I bookmarked that one for the library and will read in greater detail shortly, and probably blog on it at some point.

Lerner said...

At first blush it looks to me like GI explains the difference between the two studies: glucose drink vs "whole food". When the glucose drink provides a flood of blood glucose and glycogen stores are already topped off, then it has to go somewhere - so it gets shunted into DNLed TAG. (Note that DNL is not-so-much in the fasted state.)

Since the subjects are eucaloric, the stored TAG eventually gets burned as fuel in between feeding periods. The boobery of Taubes rested in large part on his focusing only on what gets put into adipocytes, and he never considers that without overeating it does come out for use as fuel.

Thanks to Thomas T for posting that study, because it points to the possibility of palmitate replacing *possibly* less atherogenic fat in cells and lipoproteins. Has any study examined whether small dense LDL contains relatively more palmitate? Maybe that helps to partly explain the association of pattern B with greater atherogenicity.

Evelyn aka CarbSane said...

Another thought -- if palmitate, aka the most prevalent sat fat in animal fats -- is "healthy", why is it healthy if we eat it, but somehow unhealthy if we make it? Either palmitate is atherogenic or it's not (I tend to think it's not per se, high fasting trigs are a biomarker in context of a range of western style diets). I think sat fats do influence insulin sensitivity moreso than other fats because they are the fats released from fat cells (so poor pp NEFA uptake and/or inappropriate NEFA release) and often an indicator of nutrient excess.

Thomas T said...

I don't recall it being called healthy? I believe part of the reason is that such saturated fatty acids have a very high melting point, causing issues with membrane "flexibility" at physiological temperatures

Nigel Kinbrum said...

Don Matesz made the fundamental error of talking about the melting points of various fats (he later deleted the whole post). Melting points are only relevant if the fats are in a large slab.

In the body, fats are in small globules. Think cream. Cream is liquid at 4°C. Butter is solid at 4°C.

Evelyn aka CarbSane said...

It's actually too bad he took it down only because what influences melting point, also influences particle "packing" and chylomicron size. I had a comment all set with references but the post was yanked. Maybe someday I'll unearth it and blog. It may not have any meaningful impact on health, CVD, etc., but I came across some interesting stuff.

In light of the postprandial breakdown in lipid trapping seeming to lead to excessive NEFA directly from diet, I tend to think this may be more where dietary fats matter -- in such people with malfunctioning adipose. Hopefully by this weekend I'll get that one up.

IcedCoffee said...

Interesting stuff, but I have some qualms:
The study seems to vastly oversimplify just about every topic, which always makes me skeptical. For instance, it seems to equate carbohydrate with glucose, and ignores fructose and galactose metabolism. It also seems to try to lump all dietary fats together. I haven't had time to track down the studies cited, but in the review of dietary fat metabolism, the diagram seems to suggest the fat was in the form of margarine, which makes me think trans fat.
The studies of carb overfeeding all seem to be in healthy males, and almost all are fasted. While interesting for anyone doing cyclic low carb, I doubt this is really a valid means of studying DNL.
Definitely some interesting stuff here. Wish I had more time to review.

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