Mighty Metabolism Mouse?

HERE I COME TO SAVE
THE DAY (for TWICHOO)!!

Thanks to Amber for bringing the following study to my attention: A high-fat, ketogenic diet induces a unique metabolic state in mice.   Does it appear that MightyMeta Mouse is on his way??  Perhaps ...  for mice anyway.  The KD fed mice attained the same reduced body mass as the calorie restricted (to 66% ad libitum of control chow fed) mice.  A fourth group were fed the usual high fat + sucrose diet to induce obesity.  Anthony Colpo ... pay up!?*

Animals fed ketogenic diet ate the same number of calories as animals that were fed either chow or a high-fat diet but nevertheless failed to gain weight. Remarkably, animals eating ketogenic diet lost a small amount of weight and achieved the same weight and body composition as animals that were calorie restricted to 66% of usual daily intake. Fat mass, lean body mass, levels of leptin, and glucose were the same in ketogenic diet-fed and calorie-restricted animals.

... KD fed mice had a unique metabolic and physiological profile, exhibiting increased energy expenditure and very low respiratory quotient.  Insulin levels were somewhat reduced in calorie-restricted animals compared with the chow-fed group, whereas insulin levels in ketogenic diet-fed animals were dramatically lower to a level that was only 10% of that seen in the calorie-restricted group.

Here are the intake, weights and body heat production for the mice:

The study began with 8 week old mice.  Mice are usually weaned at 3-4 weeks, so they had all apparently been eating a standard chow diet for approximately 4 weeks at the start of the study.  The first protocol (results above)  maintained them on the assigned diet for 60 days (just over 8 weeks).  They did some testing of the animals movement, etc. and determined that the well-being of the KD mice seemed to be quite good.  

These differences were highlighted by analysis of distinct metabolic pathways. In ketogenic diet animals, fatty acid oxidation and ketogenic pathways were increased, as may be expected. However, UCP2 was also increased sixfold compared with the other diets. This may have been a response to increased availability of fatty acids and increased mitochondrial fatty acid oxidation. The uncoupling and associated changes in metabolic efficiency may underlie some of the changes in energy expenditure seen in these animals.  Furthermore, fatty acid synthesis, cholesterol synthesis, and glucose-handling pathways were reduced in ketogenic diet-fed animals. Additionally, critical enzymes of gluconeogenesis, PEPCK, and G-6-Pase were suppressed, consistent with the reliance of these animals on ketones and fatty acids as energy substrates.

OK ... this change in efficiency is towards the inefficient metabolism.   It sounds like use of ketones for energy is less efficient rather than more efficient than using glucose for fuel.   

KD-fed animals had 11% higher energy expenditure than C-fed animals and 15% higher energy expenditure compared with the CR group

So, ketogenic fed animals had just over 10% higher energy expenditure vs. control chow fed animals.  If we're going to extrapolate this to humans, this would mean that if someone maintains on 2000 cal/day, and adopts an extreme ketogenic diet** they can eat roughly 200 cal/day more and maintain, or will lose some weight on KD eating at the same caloric level.  Looking at the KD v. CR, if a person fails to lose weight on 1000/1500 cal/day (as we're told repeatedly for women/men before the magical low carb mystery tour) calorie restriction, then apparently that is the person's TDEE.  Even old MightyMeta Mouse(Wo)Man, then, would burn 1150/1725 cal/day on a KD and maintain weight, or lose weight at a paultry rate of 0.3/0.45 pounds per week.

These energy differences were determined at 5 weeks into the study = day 35.  I note that KD mice lost body weight initially then stabilized out -- perhaps 5g/27.5g , or described as a reduction to about 85% initial weight in the study.  The CR mice, however, initially lost considerably more weight -- estimate 7.5g/27.5g -- which is 50% more than the KD group and over 25% of their initial weight.  This would likely trigger the often seen reduction in metabolic rate, and explain the weight rebound for the CR group.  

Now, let's talk health and body composition here folks.  As I've blogged on previously (see, for example, here), in direct contrast to TWICHOO, low carbohydrate/ketogenic diets tend to favor the fuel partitioning to fat vs. lean tissue rather than the other way around.  

MightyMeta Mouse is in Rosedale Utopia!  After just 5 weeks of the diet, the mice have next to no insulin or leptin compared to standard chow and the high fat diet.  Note: "c" is significant difference vs. HF, "a" is significant difference vs. Chow.  What did this do to the lean mass?  It dropped considerably.  The fat mass values didn't differ in a statistically significant fashion for KD v. C, but I wonder how a % fat mass or fat/lean ratio would have panned out.  (I note that when one adds up the masses on DEXA and compares these to the average body weights reported on the graphs presented earlier, there's an inconsistency there).   In any case, the KD mice lost weight, but predominantly from lean mass, seemingly preserving the fat mass if not partitioning more to that route.  I wish they repeated the DEXA at 9 weeks, but they did repeat some measures above and assessed a few more things.  

Does anything jump out at you guys on this table?? Interestingly enough, the HF group's NEFA levels seem to normalize. But KD? Well, they are elevated compared to all other diets.  But that's not the most troubling thing that I see.  How about those liver triglycerides folks??  You know what that is?  That foie gras we're all making of our livers eating the SAD?  Well, MightyMeta Mouse is well on his way alright!  The KD mice have roughly 2.5X the liver fat accumulation of their body-weight equivalent CR counterparts.   Aaaaack!!   They also have roughly 35% more liver fat accumulated compared with the poor porkster mice eating the high-fat (with sucrose!!) diet who weigh in at over 50% greater body weight compared to our KD Mighty!   Despite like no insulin -- ketogenic nirvana! -- these mice are packing the triglycerides just fine in their livers!!   

Histological analysis of the livers showed increased lipid vesicles in both HF and KD animals, and PAS staining showed decreased glycogen deposition in KD animals vs. both HF- and C-fed groups (data not shown).

The KD group appears to "scavenge" what it can and store it as liver fat.  Yum!  Now here's an interesting observation.  The second protocol took HF fattened mice and put them on the HFKD diet which reversed their obesity.  Sounds good so far.  And all the parameters improved:  lower insulin, blood glucose, etc. etc.  Still sounding great.  And then:

Paradoxically, the increase in glucose tolerance and correction of lipid profiles occurred in the context of increased hepatic triglyceride content compared with both HF and C groups.

As Scooby would say ... Ruh Roh!   Why the liver stores triglycerides rather than repackaging them for export in VLDL is a bit of a mystery to me.  Perhaps it's the liver's way of maintaining a local supply of ketone precursors in the absence of maintaining local stores of glycogen normally used to maintain blood glucose levels.  

Surely this is just a benign or temporary effect?  Well, I linked to the PDF of the study in this post.  The PDF's for studies in this journal contain a cover page including studies that reference the article.  This title kinda jumped out at me:   Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet  (sorry, abstract only at the moment). 

Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

One wonders how the life expectancy of these mice would compare to chow fed.

Oh wait!  We are not mice.  Guess we shouldn't worry that the higher liver triglycerides were accompanied by lower circulating fasting trigs in these KD mice. Lower trigs are something lots of LC'ers like to boast about.  Perhaps fatty liver is something to worry about?  Gosh after reading this I hope I didn't trash my liver doing VLC for so long.  I'm guessing/hoping not b/c I ate lower fat higher protein than most do.  

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*Anthony Colpo famously issued a challenge ($20K if memory serves) for anyone who could provide proof of a metabolic advantage in a controlled human metabolic ward study.  I'd say that these results -- a 10-15% difference at one timepoint in mice -- do not qualify.  In studies measuring metabolic rate comparing VLC to other plans, I've not seen a difference reported in humans.  AC, your money is safe!

**I would note that this diet is  5% protein, 93% fat, 2% carb.  Even the high fatties in the LC movement tend to eat more than the conventional 15% protein.  

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Follow-up post:  Is MightyMeta Mouse Relevant to Real Humans?