Is MightyMeta Mouse Relevant to Real Humans?

In my last post, I discussed a study demonstrating that mice on a ketogenic diet ate the same number of calories as both mice on standard chow and the obesogenic high fat+sucrose diet, but lost body weight comparable to that seen in mice constricted to eating 66% of the standard chow calories.  I dubbed this a metabolic Mighty Mouse of sorts, MightyMeta Mouse.  I don't think we'll have enough installments of this to warrant an acronym -{grin} - I'll just use short nicknames when I tire of typing it out.  

In any case, this study seems to validate some of the magical metabolic claims made by those who are able to eat thousands of calories on VLC diets while having been unable to lose or in some cases even maintain weight eating standard CRD level calories.  Well, I did the math in the prior post, and although Mighty does seem to manifest a metabolic advantage of sorts, this would not translate to much for the humans in question.  A couple of hundred calories a day tops, which would be nothing to sneeze at, but doesn't back up the claims some make about eating thousands more calories.

For those who've been following this blog, my not-so-near obsession with free fatty acids, NEFA, has always had me wondering what happens to all those "freed" fatty acids on a LC diet if they don't get trapped back into the adipose tissue.  They have to go somewhere, and I've yet to see evidence of significant changes in metabolic rate or total energy expenditure merely from manipulating macronutrients in human metabolic ward studies.  Therefore, if those fatty acids aren't being oxidized more rapidly enough to keep up with the excess delivery, they have to be stored somewhere.  Which means muscle, liver ... dare I wonder out loud, the pancreas?  

I've blogged quite a bit about triglycerides stored in muscle (commonly abbreviated IMTG, IMCL, IMCT -- the IM or IMC = intramyocellular, TG or T = triglyceride, L = lipid -- wish they would come up with a single designation, it would make searching the literature easier!).   One of the problems with IMTG is that there is an athlete's paradox:  IMTG is elevated in obese (women more than men apparently) and associated with IR, while in trained endurance athletes it is also elevated with no association with IR.   Mostly it appears not to be the stored triglycerides that are the problem, but the buildup of incompletely oxidized fatty acids that are oxidized (peroxidation) that cause the problems.  In any case, how does this relate to eating VLC?  I would like to see a study -- paging Drs. Westman, Volek or Phinney? -- that evaluates this both during weight loss, but more importantly in maintenance.  Would any of the prominent long term low carbers volunteer to have their IMTG (and diacylglycerol & ceramide) content evaluated?   

The basic thought process is that if the VLC'er is a "fat burner", they are burning through the fatty acids.    Certainly in weight loss it doesn't seem to be an issue as demonstrated by the improvements in IR with VLC diets seen early on.  I think the jury is still out for maintenance.  Little MightyMeta had increased lipid oxidation and downregulated fat synthesis pathways during its weight loss (~15% body weight below "normal") and maintenance phase.  However despite this, the mice did package up and store triglycerides like crazy in the liver.   It does not appear, as yet, to interfere with glucose homeostasis in these mice after 9 weeks transitioned to the diet at 8 weeks of age.

So then there was that other study, and thanks to MM I now have the full text.  I'll blog on that study separately, but to share the "human side" of the intro:
Cardiovascular disease attributable to obesity, insulin resistance, and diabetes is increasing markedly.  Insulin resistance is highly correlated with ectopic lipid accumulation, particularly in the liver.  Consequently, the pathogeneses of systemic insulin resistance and diabetes has been linked to nonalcoholic fatty liver disease (NAFLD). NAFLD is an independent predictor of cardiovascular disease, a stronger predictor than peripheral or visceral fat mass.   A critical, but only preliminarily defined, influence over the development of NAFLD and possibly its complications is distribution of macronutrient classes within the diet.  Although low-carbohydrate diets are effective for weight loss, comprehensive determination of their relationships with fatty liver remains ongoing.  The importance of further understanding the impact of low-carbohydrate diets on metabolic states in rodent and humans models is additionally underscored by case reports of humans that reveal variations in the range of metabolic response to these diets.
I note those last statements are contemporary -- this study was just published in March of this year.  So, folks, we don't know!   So this group took the same strain of mice and fed them standardly for 6 weeks at which time they were switched to the study diets for a period of 12 weeks.  Interestingly in this protocol, the KD mice increased intake vs. the other diets and the mice gained body weight throughout the 12 weeks, though slower than the other diets.   Is the liver fat perhaps benign in the context of a KD?  Again, I'll get into the specifics in another post, but I think we can all agree on the following:  excessive macrophage infiltration cannot be a good thing.   The number of macrophages in the KD livers was roughly 1.6X greater than standard chow (SC) or Western diet (WD), and the size of the macrophages in the KD livers was also roughly 1.5X greater than the two other diets.

So ... how is this relevant to us humans eating ketogenic diets?  I think one thing that can be said is that this diet is rather more extreme than anything most of even the most extreme LC dieters are eating.  The VLCHF diets seem to aim more for 70-80% fat, and although moderate protein, are likely 20% or so.  This in and of itself would change metabolic milieu considerably (but it probably abolishes any metabolic advantage we seem to see for Mighty).  Is a semi-ketogenic state as damaging to the liver?  Is this even relevant at all given the extremity of the diet used?  I would like the answers to these questions.

I remain concerned mostly with those macrophages and all the inflammation going on.  It was one thing to see the macrophage content of KD vs. SC ... it was quite another to see that macrophages were comparable between SC & WD and KD livers had more and larger macrophage content than did WD livers!  This is sobering to me.  Since this progression was apparently accompanied by decreased glucose tolerance in the mice, something long term VLC'ers seem to report with a fair amount of regularity, I do wonder if there is some relevance there.  This so-called "good physiological insulin resistance" (I've yet to see IR described as a desired state anywhere in the literature, this seems to be an invention of a certain blogger that has been picked up and repeated by others) may not be so immediately reversible or benign.  The liver, it would appear, is probably not well-suited to storing excessive fat.

Getting back to the magic metabolisms for a moment.  I note that the KD mice in the first study developed the fatty liver despite losing roughly 15% body mass (to become actually underweight) and maintaining that mass for the remainder of the study (lost weight first few weeks then stabilized out through 10th week).  Perhaps this was because of their metabolic inefficiency and the fact that they were still eating the same number of calories as the SC's??    If VLC diets are metabolically advantageous, and I were one of those making the claim of eating a lot more and weighing a lot less with VLC, I think I'd ask my doc to scan my liver.  I have no idea how this translates to the legions of low carbers who remain overweight or obese eating VLC for years and decades ...

I think this study is also at least a cautionary tale for those who do some sort of carb cycling with longer intervals and extreme cycles.  If lipid is accumulating in the liver during keto phases, what does a huge carb assault do -- top off the glycogen and switch to using that, and then what of the liver fat??  Dunno.  The LC webosphere is full of "experts" who point to the recommendation of lower fat higher carb diets as the cause of all of this dysfunction and disease.  But the problem with that is that the SAD is not and never has been consistent with the old food pyramid or the MyPlate that has replaced it.  Indeed in one simply substitutes tubers, legumes and whole grains* for what is now whole grains, there's absolutely nothing wrong with the composition of the dietary recommendations.  I would dare think that if most Americans ate that way we could eradicate this obesity epidemic in a generation.   *Real whole grains, not pulverized wholegrain flour as 10% of ingredients.

I've been experiencing a severe case of cognitive dissonance of late.  Looking into Rosedale's ridiculousness, I keep finding more and more information -- controlled studies in real live humans -- that has me almost going raw vegan (not really but you get the notion).  No, I'm not about to start eating 30 bananas a day (not that I think I even could!), but there's really not much room for argument that a LFHC diet improves glucose homeostasis and insulin signaling in most.  Where it doesn't seem to work, the solution (no matter how much I love me butter) is probably lower fat still.  All these billions of humans thriving on grains even and (at least traditionally) very low fat diets can't be written off as anomalies.

To sum up:  Is there cause for concern in these mice?  I say yes and no.  Yes because the changes in the livers are disturbing and we don't really know if it's the extreme fat content of the diet, the protein restriction, or the reliance on ketone metabolism for energy.  But perhaps no, because the diet they were on (<5% protein, >90% fat) is a far cry from the diets of practicing "ketogenic" low carbers who probably aren't in anywhere near the ketogenic state they aspire to be in anyway.

To be continued ....

Ketogenic Diets & Fatty Liver


Mario Iwakura said…
Hi Evelyn,

Have you seen this?

The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study.

"complete fatty liver regression was observed in 21.4% of the patients, and an overall reduction was found in 92.86% of the patients"

Description of the "Spanish Ketogenic Mediterranean Diet" here:

"This Ketogenic diet was called "Spanish Ketogenic Mediterranean Diet" (SKMD) due to the incorporation of virgin olive oil as the principal source of fat (> or =30 ml/day), moderate red wine intake (200-400 ml/day), green vegetables and salads as the main source of carbohydrates and fish as the main source of proteins."
CarbSane said…
Hi Mario! You're a step ahead of me. I hope to get to blogging on the new (to me) info on MUFA and glucose homeostasis and all that. I believe it was you (or was that the other Mario?- grin) who said the results of Shai may have been attributable to MUFA. There seems to be a lot more to this type of fat than meets the eye. I'll have a look at those studies, thanks!
Mario Iwakura said…
Hi Evelyn,

MUFA? No, If I remember correctly, I speculate about high PUFA content of the Shai study.
CarbSane said…
Hmmm ... I'll have to look back on that. Will do after eating me some safe (and a few not so safe) starches tomorrow! Anyone who can forego my sister's pecan pie is a better (wo)man than I!!
Anonymous said…
Hi Evelyn,

Im skeptical of the results in that mice, given the physiopathology of NAFLD and the evidence in humans:
sixty-five said…
Thank you for the last two paragraphs, for those of us who are science-impaired. As much as I am impressed by all the biology, what I really want and need to know is: what's the takeaway? What WORKS? I am eating pretty much "perfect health diet" myself, and continuing to lose while eating moderate amounts of "safe" starches. And watching the portion sizes.
Sanjeev said…
the diet you stick to for life plus extra physical movement you can do for the rest of your life.
CarbSane said…
Hi Lucas, I'll take a look at those after the holiday.

Yes, sixty-five, I know lots of science goes on here but I do try to keep a tether on what it all means in the end.

Oh, Mario, now if memory serves you mentioned why the Med group may have done better was their MUFA from olive oil. Will search the reader ;)
Mario Iwakura said…
I think that the comment you are refering is this one: