How Keto Works 👀 - Or How It Seems To or Could or Might, Evidence

(Michael - When reality fails to meet expectations, the problem is not reality.) #1

Summary

Despite the relative lack of clinical data, there is an emerging literature supporting the broad use of the KD (and its variants) against a variety of neurological conditions. These preliminary studies are largely based on the fundamental idea that metabolic shifts may lead to neuroprotective actions (Gasior et al., 2006; Maalouf et al., 2009). How can a simple dietary change lead to improvement in disorders with such a huge span of pathophysiological mechanisms? Alterations in energy metabolism appear to be a common theme. So while the mechanisms through which the KD exerts such effects are likely diverse (Maalouf et al., 2009; Rho and Stafstrom, 2011), there may indeed be one or more common final pathways that are mechanistically shared. Ultimately, the details of how that altered metabolism reduces neuronal excitability, abrogates ongoing neurodegeneration, or mitigates functional disability remain unknown. Herein lay rich opportunities for further investigation, in both the laboratory and the clinic, in the broad realm of translational neurosciences.

I include the following because it has 70 citations, mostly epilepsy-related. But I want to mine this citation list for whatever I can find. My first ‘find’ was the above link.

(Bacon is a many-splendoured thing) #2

These are very interesting articles. Thanks for posting these links.

I’m glad that the second article mentions the fact that a classical ketogenic diet (i.e., one that provides an adequate protein intake) is an effective treatment for epilepsy, because the standard epileptic ketogenic diet is so low in protein that it has damaged the growth of some children.

(Michael - When reality fails to meet expectations, the problem is not reality.) #3

…The finding that humans have active brown fat has raised high expectations for the treatment of obesity-induced diseases, since brown fat can dissipate caloric energy and reduce both obesity and diabetes in experimental animals [8–12,37–40]. In fact, after short-term cold exposure, brown fat is the main lipid clearance organ [16]. Thus, recent years have seen increasing interest in the regulation of BAT thermogenesis. Most of the strategies have been focused on the role of UCP1 and attempts to enhance heat production, although other authors argue that additional genes may cooperate in the thermogenic function [41].

The finding that BAT is the tissue with the highest FAO rate [42] and that the activity of the FAO rate-limiting enzyme, CPT1, is decreased in BAT of diabetic rats [32] led us to hypothesize that BAT thermogenic power could be enhanced by increasing its FAO.

(Michael - When reality fails to meet expectations, the problem is not reality.) #4

Obesity is simply understood as an imbalance between energy intake and expenditure in favor of weight accretion. However, the human biological interface between food consumption and energy dissipation results in broad individual differences in eating behavior, physical activity, and efficiency of fuel storage and metabolism. In particular, the basal metabolic rate, which accounts for the greatest portion of overall energy expenditure, can vary almost twofold among individuals. Classically, three major biochemical systems are believed to contribute to basal thermogenesis: futile cycles, Na+/K+ATPase activity, and mitochondrial proton leak. The latter is the most important quantitative contributor and can explain up to 50% of the basal metabolic rate (1). The molecular basis of mitochondrial proton leak is unclear, despite its importance in the understanding of energy balance and its potential as a therapeutic target for obesity treatment. The article by Hesselink and colleagues in this issue of the JCI (2) addresses whether uncoupling protein 3 contributes to mitochondrial proton leak in human skeletal muscle.


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What is the role of UCPs?

… Another exciting hypothesis is that UCP3 could facilitate lipid oxidation by acting as an FFA anion transporter. Elevated circulating FFA levels are associated with increased muscle UCP3 expression in a variety of physiological states (fasting, high-fat feeding, lipid infusion, diabetes, obesity) independent of any changes in energy expenditure (3, 17, 18).

(Michael - When reality fails to meet expectations, the problem is not reality.) #5

This is a mouse study, so the usual caveats apply. It is still quite interesting. It compares glucose and fatty acid uncoupling efficiencies.

Conclusions— These data indicate that reduced mitochondrial oxidative capacity may contribute to cardiac dysfunction in ob/ob mice. Moreover, fatty acid but not glucose-induced mitochondrial uncoupling reduces CE in obese mice by limiting ATP production and increasing MV̇o2.

In case it’s not clear, this is not a pro-keto study. This study tested the extent of fat accumulation in the heart muscle, which contributes to decreased function, by both glucose and fatty acid oxidation. The conclusion is that fatty acids contribute more in the obese mice due to mitochondrial uncoupling of fatty acids by “limiting ATP production and increasing MV̇o2”. I think it’s significant because it demonstrates that uncoupling of mitochondria via lipolysis leads to greater oxidation of fat and less ATP than that of glucose. That is: the metabolic advantage of keto.

(Bacon is a many-splendoured thing) #6
(Bob M) #7

Ah, dude:

From Ben Bikman’s lab. They demonstrate uncoupling in cells, rats, and humans.

(Michael - When reality fails to meet expectations, the problem is not reality.) #8

Actually, Bikmans’ video that Paul linked above was my inspiration to start this topic. I had posted a link to the same video in another topic. I think these guys are onto the secret here. :thinking:

(Doug) #9

In conclusion, these results indicate that ketones elicit a pronounced and perhaps even meaningful shift in mitochondrial function in adipose tissue. Whereas adipose tissue is generally a low metabolic rate organ that stores energy, ketones enable a fundamental and uncharacteristic shift towards energy wasting via the initiation of a futile cycle by increasing electron transport but not ATP synthesis. These findings shed light on previous observations of enhanced energy expenditure in ketogenic states, and may provide novel interventions in the future to help combat the growing trend of obesity and derivative disorders.

Bikman rules :prince: - this, along with the response to protein (insulin/glucagon) when keto and non-keto, is truly an eye-opening thing.

“Energy wasting,” though - imagine more of that when the body is using its own fat. They do address this:

These results are thought-provoking when viewed through the lens of starvation. Food restriction is the most rapid stimulus for ketogenesis. Of course, in such a state of energy deprivation, it is difficult to imagine the body wasting energy through ketone-induced adipocyte mitochondrial uncoupling. Interestingly, short-term starvation (i.e., fasting) paradoxically increases energy expenditure. Zauner et al. found that energy expenditure increased throughout the first two days of a four-day fast and remained elevated until the end. Coincidentally, plasma ketones followed a similar trend. However, the phenomenon has a limit—long-term starvation, such as that seen with anorexia nervosa, is associated with a reduction in the metabolic rate. There are certainly other factors that mediate some of this effect, such as reduced muscle mass, but a relative insufficiency of adipose, and the lipid substrate for ketogenesis, may also be relevant.

The increased energy expenditure during fasts does seem to lessen or even reverse over repetitive fasts, however, in at least some anecdotal cases. @primal.peanut - Neil, as I recall your metabolism ended up declining (500 cals/day) when fasting, and that there was even an anticipatory effect…?

a relative insufficiency of adipose… may also be relevant. Certainly could be a factor - one would think that a really lean person’s body would be more loathe to ‘waste’ energy. Good thing for a study to address.

In the end, though, this all makes a keto diet look even better, for most of us. :+1:

(Michael - When reality fails to meet expectations, the problem is not reality.) #10

I described my personal experience with calorie deficit here:

I think the really significant thing is my experience (or lack of experience) of hunger. One of the common experiences of folks on mod-high carb low fat calorie restricted diets is they’re always hungry. I think they experience severe hunger because they’re not accessing endogenous fat efficiently. I think the number is something like 30 calories per day per pound of fat. That’s not much unless one is very obese, but it’s enough to prevent instant starvation. And they do lose fat slowly over time. But the body is screaming “Feed me! Feed me now!” just like that flesh eating plant in Little Shop of Horrors.

On the other hand, being in ketosis freed up my endogenous fat stores for easy and efficient access. My metabolism, even in a 1000 cal per day deficit, still had plenty of incoming fuel. So, no demand to be fed. Of course, at some point had I continued the deficit I would have run out of endogenous fuel. I think at that point, I would have started to experience hunger, my metabolism slow, and utilization of endogenous fat drop to minimal.

I lost on ave about 1.5+ pounds per week for 3 months (12 weeks). Using 3500 cals per pound (yes, I know that’s off, but it’s all we’ve got to work with), that 1.5+ pounds was approx 5-5.5K calories per week. So about 900-1000 calorie daily deficit. So even the math is close enough. Was I accessing more than the 30 cal per day per pound of endogenous fat? Maybe. I didn’t have much to start with, but burned it efficiently. How much of that was just being wasted? I don’t know, but probably more than enough to measure.

Weight gain woes..help me!
(Bacon is a many-splendoured thing) #11

BTW, some terminological correction, sorry!

While “glycolysis” means the metabolising of glucose, the equivalent term for fat is “fatty-acid metabolism.” The reason is that the term “lipolysis” refers to the breaking-apart of triglycerides into their three fatty acids plus glycerol backbone.

As far as protein is concerned, “proteolysis” refers to the separating of a protein into its constituent amino acids, which must then be “deaminated” before the remnants can be metabolised.

(Michael - When reality fails to meet expectations, the problem is not reality.) #12

Noted. Thanks.

(Bob M) #13

I also wonder what happens over time.

In Bikman’s group’s paper, they recruited people with “long-term self-adherence” to a ketogenic diet, but their ketones were 1.8 +/- 0.3 mmol/L, measured by the Precision Xtra meter (which I have). After almost 7 years LC/keto, I get less than 0.5, usually 0.2 or 0.3 in the mornings and higher in the evenings. I didn’t take data for a few years in the beginning, and when I started taking data, I could get those levels in the morning. But I haven’t seen a 1.8 in the mornings for a long, long time, unless I’m fasting 4+ days.

I wonder if this means I’m now uncoupled from my mitochondrial uncoupling? :wink:

(Bob M) #14

Yet another unanswered question: does the level of ketones affect the amount of uncoupling? That is, does a higher level of ketones mean there is more uncoupling? If so, maybe there IS a reason to chase ketone levels.

(Neil) #15

I captured my experience with measuring my RMR every day during serial 5-day fasts in this thread:

https://www.ketogenicforums.com/t/neils-extended-fast-tracker/85327

I measured RMR first thing every morning. In general my RMR was highest the morning after I feasted, then dropped around 400 kcal/day the following day, then came back up again, then gradually went down. But it’s entirely possible that the 400 kcal/day drop after 1 day of fasting was due to me eating chocolate during my feasts and throwing my metabolism off that way…

(Bacon is a many-splendoured thing) #16

I haven’t heard anyone say that it does. I understood Prof. Bikman to be saying that the uncoupling is the result of excess available energy, but that may simply be me hearing what I expect. On the other hand, Verdin and others have shown the epigenetic effects of the various ketone bodies, so you may be on to something.