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Monday, March 7, 2011

Ketogenic Diet increases Fat Mass and Fat:Total Body Mass Ratio

Ketogenic diet-fed rats have increased fat mass and phosphoenolpyruvate carboxykinase activity


This study looked at body weight, fat mass, blood lipid and glucose levels and PEPCK (rate limiting enzyme in glyceroneogenesis pathway for G3P production for esterification of fatty acids - fat deposition) activity in the liver and fat cells.  Two ad libitum diets were compared, a control standard chow and a ketogenic zero carb chow.  This study was in normal, young (30 days old at start) Wistar rats and lasted 6 weeks.

The diet compositions are shown below:


I've included this because in the past, the fat used in such diets has been PUFA or transfats so the results have been dismissed as due to the unhealthy fat content of the diets.  In this case, however, the fat was mostly the "healthy fat" lard.  Protein content was comparable by weight, though it would appear to be different by percent as carbs were apparently "swapped" for fat on a g-by-g basis.

So here were the results:

In the top plot we see that the KD rats gained less total body mass, but in the middle graph we see that they gained more fat (epididymal and perirenal fat = visceral fat in rats) leading to a significantly higher FM:TM ratio as shown in the bottom graph.  I would note that not only is the ratio greater, but the trend was towards increasing the ratio as time went on and the slope of the trendline would indicate this worsens with time.

One thing this study shows is that glyceroneogenesis is perfectly capable of providing the G3P needed to deposit fat in the absence of dietary carb.  PEPCK was elevated in fat cells (but not liver).  The rats didn't become obese on this VHF diet, but they got fattier.  This is that fuel partitioning that Taubes is now talking about as being how carbs make us fat because insulin makes fat accumulate.  Only this shows just the opposite of Taubes' claims.  It was the zero carb rats who partitioned more food calories to fat vs. lean mass. The insulin riddled rodents grew more, but partitioned their fuel towards lean mass.  These results are similar to what was seen in mice following mild calorie restriction.  Perhaps the carb restriction is sensed as "starvation" by the rats' bodies?

In any case, by the sixth week, the KD rats had accumulated 2.4X the fat mass than their carb and insulin ridden counterparts.

Interestingly enough in this study, the blood lipids were comparable (and the controls had higher HDL).


Not surprisingly, the KD rats had impaired glucose tolerance as determined by an intraperitoneal (injection into body cavity) glucose tolerance test.  This was likely attributable to insulin resistance.

The authors describe the fat deposition as being "TAG saving activity" - in response to necessarily elevated FFA's,  So the rats accumulate fat to maintain normal circulating lipids.  I'm comforted to learn that ectopic fat deposition does not seem to occur with the ketogenic diets, however I'm not keen on visceral fat deposition!  Perhaps this visceral "buffer" is the body's adjustment to greater lipid turnover in the "fat burning" metabolism. 

In any case, this study and the results really flies in the face of the insulin-centric theories of obesity.  Although the KD rats started to accumulate fat, they did not become obese, just fattier.  The fat accumulation didn't spur overeating to continue the horizontal growth.  The rats with reduced insulin and no dietary carbohydrate were more efficient "fat trappers" than those with the most insulin and a boatload of dietary carb.  

The authors gave due diligence to the limitations of their study that I'll copy here:
It is important to mention some limitations and perspectives of this work. Firstly, the normal lipidemia observed does not necessarily reflect a normal storage or distribution.  Moreover, most of the data available regarding PEPCK regulation are in rodents, thus elevated adipose glyceroneogenesis and its consequences deserve further investigation in humans. 
Secondly, the visceral lipogenesis was accompanied by glucose intolerance. This apparent insulin resistance also has been reported in KD-fed rats subjected to insulin-induced hypoglycemia [42]. On the other hand, an increase in insulin sensitivity has been described in children during KD [43]. Thirdly, it is important to mention that KD is not prescribed ad libitum to children refractory to conventional anti-epileptic drug treatment. In fact, some authors have proposed KD with caloric restriction to investigate and to obtain the anti-epileptic effect of this diet [9].  In our study, rats received ad libitum ketogenic or regular diet. Caloric restriction per se appears to induce an increment of hepatic PEPCK activity [44].  Possibly KD with caloric restriction also increases adipose PEPCK activity.  However, this issue also deserves further investigation.

13 comments:

Christian said...

"In any case, this study and the results really flies in the face of the insulin-centric theories of obesity."

At least in rats. ;)

But I think it's true. Like Lyle McDonald says, you can get shredded on an all-carb diet and fat on a zero-carb one. No problem.

Obesity still remains a multifactorial problem and the insulin-obsession might be somewhat misplaced. But that doesn't rule out the possibily that anything that effects insulin-signalling -can- be a strong contributor in the development of obesity.

Alan said...

I think its telling that four of your top five posts are related to your Gary Taubes obsession.

Without Taubes, no one would have paid you and your thin arguments any mind.

Arrogant Prick said...

This is an interesting article. I'm definitely not much of a biology person, but it seems that this wouldn't be a good comparison for ketogenic diets vs carb rich diets, if that was their intent. What I think is interesting is that (unless my math is wrong or read something wrong) that the KD rats gained less weight while consuming about 75% more calories.

KD
695*9 = 6255 Fat calories
240*4 = 960 Protein calories
6945 = total calories
235g (end weight) - 110g (starting weight) = 125g weight increase


Control
110*9 = 990 fat calories
220*4 = 880 protein calories
520*4 = 2080 carb calories
3950 = total calories
285g - 110 = 175g weight increase


Calorie comparison (KD/control)
6945/3950= 1.758 = 75.8% more calories for KD


Calories/weight increase

KD
6945/125 = 55.56

Control
3950/175 = 22.57

55.56/22.57 = 2.46 = 146% KD over control (calories/weight increase ratio)

in other words, calorie for calorie, KD calories contributed to weight gain at a rate of 40.6% or 1/(2.46) relative to control

Also, being that at 4 weeks, these are very young and growing rats. I would expect they would need exposure to insulin to realize considerable muscle growth, so the fat mass/body weight ratio would be in favor of the group receiving carbohydrates.

This would be an interesting to see this test if they were starting at an adult/full-growth age and the groups consumed equal amounts of calories.

CarbSane said...

Welcome AP! The compositions were g per kg food, but the rats were fed ad libitum so we don't know the total caloric intake. The two diets worked out to KD: 10% protein, 90% fat and standard: 22% protein, 25% fat, 53% carb.

I think the reason this was done in young rats was to make it somewhat more relevant to the use of this diet in kids, but yes, it would be interesting to see the impact on "adults". One problem with those studies in rats is that they continue to grow in size while we humans don't.

I think the stunted growth we see in both in these rats and epileptic kids on keto diets is due to protein insufficiency.

Wish they had measured energy expenditure for these rats!

Arrogant Prick said...

Ah. I assumed I was misreading something, as I didn't think a 110g rat could eat 700 calories. I shouldn't read studies at 2 AM. It would be nice to know what the caloric intake was as I think that is relevant.

Yeah, I would guess there would be much improved WAT results from the KD group if they increased the protein to fat ratio, as it would increase insulin to allow muscle hypertrophy, but I suppose it wouldn't be ketogeneic anymore if protein became to high.

CarbSane said...

@Alan: Those "Top 5" are all time page hits. I have little control over what is more or less popular there. Frankly I'm proud that the Nutrient Fates remains up there on the list.

But just to put things in perspective here, more people have read this blog in the past three days than have read my number 1 post, and that readership level has been pretty consistent for quite a while now.

Judging from the "spread" on a daily basis, I have readers with quite varied interests. Obviously you keep coming back ........

CarbSane said...

I would guess there would be much improved WAT results from the KD group if they increased the protein to fat ratio, as it would increase insulin to allow muscle hypertrophy, but I suppose it wouldn't be ketogeneic anymore if protein became to high.

Not sure there can't be a happier medium there utilizing MCT's a bit more. This is pure speculation, but it seems our bodies sense protein and/or carb deprivation after some period of acclimation (this study and the mouse CR one I linked to in the post) and go into sequester vs. build mode as a result.

Sanjeev said...

> would increase insulin to allow muscle hypertrophy

If the rats were not being weight trained why would they get hypertrophy?

I would assume high protein rats might have a little more muscle than those fed low-protein diets, but without specific stress to trigger anabolism, without being weight trained for example why would they get hypertrophy?

kds said...

CS: Epileptic kids on keto have stunted growth not only because protein is deficient, but also because keto only controls epilepsy particularly well when the diet is maintained at 80-90% daily caloric need. There are a few animal studies and anecdotal evidence in kids demonstrating that ad lib (or miscalculated) diet regimens are ineffective.

Arrogant Prick said...

Sanjeev said...

> If the rats were not being weight trained why would they get hypertrophy?

> I would assume high protein rats might have a little more muscle than those fed low-protein diets, but without specific stress to trigger anabolism, without being weight trained for example why would they get hypertrophy?

I believe the rats in the study were just 4 weeks old at the start and it lasted for 6 weeks. I think rats hit puberty at around 6 weeks of age.

I don't know if they get much stimulus in the cage, but I think there would be some significant muscle hypertrophy during 4 to 10 weeks of age, which I am guessing was likely stunted without insulin and from IR due to no carbs and very limited protein.

If the study started with adult rats, I would guess the WAT/Body Weight would be different, but that wasn't the point of the study.

M & M said...

The skates is due to the protein, which is in excess.
Here is proof http://www.ajpendo.physiology.org/content/292/6/E1724.full
Amino acids = enzyme produces glicerolo-3-phosphate from pyruvate, derived mainly from the catabolism of carbon skeletons of amino acids,large amounts of alanine, which gets the liver and converts it into glucose.

Glukogenne amino acids: alanine, arginine, aspartate, cysteine​​, glutamine, glutamate, glycine, histidine, methionine, proline, serine and valine

Amine groups are converted to ammonia, from which the liver produces urea, then excreted in the urine. The same changes are taking place at the feeding of excess protein, which utilizes no human system for the purpose of building blocks. In this case, the deamination of the carbon skeleton is formed in the course of glucose changes and the current lack of demand for energy - the fat deposited in adipose tissue as an energy reserve. Therefore, consumption in excess of expensive, high-protein products may contribute to the formation of overweight and obesity

Evelyn aka CarbSane said...

Hi M&M ... "skates"?

M & M said...

My englisch is bad :)

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