Monday, November 21, 2011
Impaired Mitochondrial Function and Obesity, Part Two
Several types of mitochondrial defects have been observed. These are summarized by M.M. Rogge and by J.A. Houmard in their review articles. (The picture above comes from the Rogge article.) Both reviews cite a 2002 study by Kelley et al. that used electron microscopy to show a 35% decrease in skeletal muscle mitochondrial area in obese vs. lean subjects. In some obese subjects, but not lean subjects, there were also large vacuoles which appeared to be degenerated mitochondria. Obese subjects also tended to have mitochondria with less clearly defined inner structure and narrower cristae.
The reviews also cite a 2005 study by Ritov et al. showing lower mitochondrial DNA content (fewer mitochondria) in obese subjects and reduced electron transport chain activity of the mitochondria, even after adjustment for the reduced mitochondrial content. This is consistent with a number of studies that show an increase in activity of certain glycolytic enzymes and a decrease in activity of other enzymes related to oxidative function in obese vs. normal-weight subjects. (See the two review articles for lots of references.) One of the important enzymes that has a lower activity in obese subjects is carnitine palmitoyltransferase 1 (CPT1, the smallest green rectangle in the drawing above), the enzyme that regulates and facilitates the entry of long-chain fatty acids into the matrix of the mitochondria.
To summarize, there are several possible reasons that obese people may have a harder time oxidizing fatty acids than they should. (1) They have fewer mitochondria. (2) They have smaller mitochondria. (3) Their mitochondria have structural problems that are visible by electron microscopy, and some of their mitochondria may even have degenerated completely. (4) Their mitochondria have reduced oxidative activity.
So far, I have painted a fairly bleak picture. It’s even bleaker when you read the articles I’ve referenced and realize that while metabolic flexibility is poor in obese people, it’s even worse in people with type 2 diabetes. (I’ve cited only the lean vs. obese in this discussion, but many of my citations also include a type II diabetes group as well, and these typically perform worse than the obese subjects do.)
It’s possible that some people have a genetic predisposition against metabolic flexibility. However, because obesity and type 2 diabetes become more prevalent with increasing age, it’s also possible that we are gradually poisoning our mitochondria, so that our surviving mitochondria are the ones that prefer to metabolize carbohydrates. These survivors not only tend to shunt fatty acids into storage, but they also resist metabolizing the fatty acids that are mobilized out of storage between meals. Our low energy production (and the easy availability of food) encourages us to eat more carbohydrate to provide the ATP we need for daily life. We could propose various possible mechanisms for gradual mitochondrial poisoning but at this point it is only speculation. In any case, we can’t change our genetics, and we can only hope that what we currently call a healthy lifestyle is genuinely healthy for our mitochondria.
On the positive side, there do seem to be a few things we can do to improve our metabolic flexibility. The first of these is mild-to-moderate exercise. In 2007 Solomon et al. described a 12-week program of moderate aerobic exercise in older obese people that improved (decreased) their respiratory quotient by 0.04. In 2010 Meex et al. asked older male type 2 diabetics to exercise twice a week for 30 minutes on a cycling ergometer and to perform resistance exercise once a week. Before the training program, their metabolic flexibility was about 60% of that of a group of matched controls. After twelve weeks, their metabolic flexibility was the same as that of the control group, and the protein content of their electron transport chain proteins had increased by 275%.
It is possible that more vigorous exercise may not be as helpful as mild-to-moderate exercise for restoration of metabolic flexibility. When the body’s AMP to ATP ratio increases, it activates adenosine monophosphate (AMP) kinase. In order to restore high ATP levels, the AMP kinase does a number of things including downregulation of physical activity and upregulation of feeding behavior. Because of this, it may be necessary for a mitochondrially impaired individual to titrate their exercise so that there is just enough to promote mitochondrial flexibility but not so much that it would cause an AMP kinase-mediated drive to eat more and exercise less.
Once metabolic flexibility is somewhat restored, it is important to take advantage of it. Because carbohydrate will always be metabolized first, it makes sense to decrease the availability of this substrate to the mitochondria. Meals should be low in carbohydrate, moderate in protein and relatively high in fat, to keep the mitochondria in fat oxidation mode as much as possible. Snacks should be avoided because each time carbohydrate is consumed, it moves to the front of the line in the mitochondrial queue. (For an interesting discussion of the effect of exercise, high-fat meals and improvement of the respiratory quotient in healthy young men, see Smith et al.)
As mentioned earlier, carnitine palmitoyltransferase 1 (CPT1) is a major control point for the entry of long-chain fatty acids into the mitochondrion. A third strategy for improving fatty acid oxidation is to circumvent CPT1 by consuming medium-chain fats like coconut oil and butter, rather than fats that contain long-chain fatty acids. Medium-chain fatty acids are metabolized differently than long-chain fatty acids because they can diffuse across plasma membranes without the help of transporter proteins. Thus, they can find their way into the mitochondrial matrix and present themselves to the beta oxidation machinery, to the TCA cycle, and to the electron transport chain without the need to deal with gatekeeper CPT1 proteins that are either downregulated or present in insufficient amounts. According to Houmard, circumvention of the CPT1 chokepoint may be helpful in increasing fatty acid oxidation and decreasing insulin resistance. However, this line of reasoning involves a fair amount of handwaving and probably needs a clinical study or two to back it up.
There it is. Mitochondrial dysfunction may be a plausible explanation for some forms of obesity. If mitochondria fail to oxidize fatty acids, both ingested and de-novo synthesized fatty acids will be preferentially routed to and will tend to remain in storage. The fact that weight loss by itself does not improve fatty acid oxidation in mitochondria explains why it is so easy to regain weight on a diet that is fairly high in carbohydrate. The fact that mitochondrial defects can be accumulated over time explains why a person can eat all sorts of foods and remain a normal weight while he or she is young, but when middle-age approaches, as often as not, so will the middle-age spread.
There are lots of other explanations for obesity, and this may not be a definitive one. But if you suspect that it might apply in your own case, it may be worth it to try (1) a mild-to-moderate level of exercise, (2) a low-carb, moderate-protein, high-fat diet and (3) replacing some of the long chain fatty acids you've been eating with medium chain ones. Enjoy that exercise machine or walking program and bon appétit!
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Is there benefit with supplementation of coq10 and L-Carnatine?
I honestly don't know, Stephanie. In the comment section of my previous post, majkinetor gave some recommendations for several supplements, but I haven't had the time to check them out yet.
Got it, thanks. Thanks for the post too.
Nice post (as always).
Two issues I would like to raise, however. The first is to question the idea that easy to moderate exercise is the key to mitochondrial rehab. We know that mitochondrial proliferation is enhanced by maximal effort (such as High Intensity Interval Training). If I were trying to rehab my mitochondria, I would definitely include HIIT as the first order of business. (Some lower-intensity exercise would be good, too, just to keep the calorie burn up.)
I would also be inclined to cut my carbs so as to select for the mitochondria that are more efficient at handling fatty acids.
I know that the current theory is that, except in rare cases of heteroplasmy, the mitochondria in any individual are all genetically identical. This doesn't necessarily mean they are all functionally identical, however; and the elaborate exchange of information between mitochondria and the actual cell nucleus might allow for a great deal of variation. (Have you read Nick Lane's "Power, Sex, and Suicide" on mitochondria, btw?)
In other words, it may be that people are obese because their mitochondria are poor at processing fat; but I find it equally plausible that mitochondria poor at processing fat have been selected for in the process of becoming obese.
So, I'd try to up mitochondrial biogenesis (HIIT), and also ensure I created an environment where high fat competence was either encouraged or selected for (LC).
HIIT > injure yourself (eventually)
my take? low intensity movement + body-weight training + regular DIF in the context of a super high FAT and protein, diet with a moderate carb intake.
Hi, David. Thanks for your thoughtful comment.
You said that mitochondrial proliferation is enhanced by maximal effort. While that may be true for lean, healthy males, it may be a more difficult goal for people whose mitochondrial function is already damaged. And, as pabloDLS said, injury is always a possibility. In a practical sense, it might be wise to start with low-intensity exercise and try different regimens as metabolic flexibility improves.
I don't think all mitochondria in an individual are genetically identical. There are multiple copies of the 37-gene-encoding circular mitochondrial DNA within each mitochondrion. There is also a fairly high mutation rate (microheteroplasmy) of the mitochondrial genome, and these variants would probably be expressed differently depending on the time of the mutation and the tissue in which it happened. It's also important to remember that most of the 1500 proteins within a mitochondrion are coded in the nuclear DNA, and each of these may come from either the maternal or paternal gene. At any rate, all of these variables mean that the mitochondria within one individual can be quite different from each other.
No, I haven't read Nick Lane's book. It sounds a bit too philosophical for me, but from the reviews at Amazon, it provides an engaging explanation of the inner workings of mitochondria.
I have an inherited neuromuscular disease that affects the mitochondria, CMT2A2. I am 69, no longer walk and am losing the use of my hands. And, I'm about 40 pounds overweight and can't budge it even on a 1200 calorie a day diet and a specialized weight loss clinic. After 8 months and only 5 pounds off, they explained to me that because my mitochondria was affected, I'm aging and can't really exercise (resistance only) it was impossible to lose it. I don't believe that. There has
to be a way to boost my compromised mitochondria and give them what they need to function more efficiently. What can I do? I need to know, in laymen's terms, what foods will aid my mitochondria. I need to know what to ingest to help them. Please, can you help. There is plenty of information on my type of CMT, but nothing on what to do if you have it. I'd like a few more useful years and I won't have them if I can no longer use my hands or lift myself. Thank you.
Linda, I'm sorry to hear about your condition. Unfortunately, I'm not a physician of any kind. I'm only a biochemist. I offered a few suggestions at the end of this blogpost, but I have no idea if they would work for you or not. You might print off Parts One and Two of my discussion, present them to the physicians who follow you for CMT2A2, and see what they think of my suggestions as possible strategies for partial restoration of mitochondrial function. I wouldn't want you to hurt yourself inadvertently, so please be very careful.
LindaC., I just looked at your profile. You just registered with Blogger in November 2011 and have only had two people look at your profile. If you haven't been around the low-carb community very long, some of the discussion here may be unfamiliar to you. When I talk about a low-carb/moderate-protein/high-fat diet, I'm talking about something very similar to the original Atkins diet. All of us in the low-carb community modify it to meet our personal idiosyncrasies, but the ins and outs of it are summed up in Dr. Atkins' Diet Revolution and Dr. Atkins' New Diet Revolution.
I have no idea if this type of diet will help with your health situation, but if you want to become familiar with what the low-carb way of life is and how to do it, reading those books is the best place to start. They can both be found on Amazon. And do consult with your physicians if you decide that low-carb might be helpful. They know far more about Charcot-Marie-Tooth disease than I could ever hope to.
Hi - I've been following a low carb diet for years. That's also what the special diet clinic promoted in a big way but no one suggests any kinds of fats except oils. I actually crave beef sometimes. Rare beef. I've read Atkins and Oz and many others and subscribe to Nutrition Action, an excellent newsletter. I'm even going to be growing my own greens next year in a raised garden box so I can tend while sitting. I have printed off both of your articles and will digest and ask questions.
My CMT docs know nothing about nutrition. It's up to me. I take 200 mg a day CoQ10 and that helps my breathing a great deal plus I take other supplements. B6 can make my condition worse so I don't take a multi-vitamin to avoid that. I work around it and my diet is excellent. I don't smoke or drink alcohol as it's toxic to my already compromised nervous system. Coffee, tea and chocolate (anything with caffeine) makes my pain worse.
I know you're not a doctor, and doctor's can't help me as there is treatment or cure for what I've got, but could you give me some idea of where to get the good fats I need to perhaps allow my mitochondria to function a little better?
As I read more about CMT2A2, I'll ask more questions, if I may. I think I'll be speaking your language more as I go. It's a whole new world out there when you get into medical journal articles and biochemistry.
Thanks for your reply, LindaC. The only recommendation I might have is medium-chain triglycerides (coconut oil, palm kernel oil, butter) instead of the more conventional oils. As I said, there is a bit of handwaving rather than scientific evidence that these can more easily cross the two mitochondrial membranes and don't particularly need a transport system to do so. But it might be worth a try to see if they improve your metabolism.
I wrote about coconut oil here. If you decide to try it, introduce it *slowly* into your diet--just a teaspoon for a few days. If you tolerate that, move it up to two teaspoons for a few days. Et cetera. Too much coconut oil too fast can cause gastrointestinal symptoms, so moving it up slowly is better. Some people can't tolerate it at all, but some people love it. I eat four tablespoons per day, and most of the rest of my fat intake is butter.
Again, check with your doctors. They may wave their hands in horror because these fats are highly saturated, so be prepared for that. As I said, I don't have much scientific evidence that this works with dysfunctional mitochondria, only logical inferences. Best wishes.
Sorry to bombard you but here's a description of CMT2A2 that might shed some light on it diet wise.
"CMT2 results from abnormalities in the axon of the peripheral nerve cell rather than the nerve sheath. It is less common than CMT1. CMT2A, the one I have, is the most common axonal form of CMT, and is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion. CMT2A has also been linked to mutations in the gene that causes the kinesin family member 1B-Beta protein, but this has not been replicated in her cases. Kinesins are proteins that act as motors to help power the transport of materials along the cell."
Knowing this, I'm wondering if there are some things you can think of that I can supplement my low carb diet with to enhance mitochondrial function rather than impede it?
Thanks for breaking it down. I've read Peter's blog-Hyperlipid where he's discussed MC, but I could never figure out exactly what the problem was, until your explanation.
It seems like on a LC diet, mitochondria mal-adapted to lipid oxidation may cause apoptosis to adipocytes, escpecially if there are a large number of crap MC's in an adipocyte.
I'm interested in adipoptosis because in my own n=1 I believe that adipocyte hyperplasia may be reducing FFA's and leptin which makes maintenance difficult on an ad-libitum diet. But the science can't even agree on hyperplasia yet, so it's still decades away from helping me with maintenance.
Probably, the best butter for would be the one made out milk of grass-fed cows (Kerrygold or Organic Valley pastured butter) because it has the best lipid profile.
I found Lane's book quite enjoyable, despite the tongue-in-cheek title. His discussions on the evolution of apoptosis (including the voluntary "suicide" of mitochondria) as a needed stage in the development of multicelluar organisms was fascinating.
As to high-intensity training, there are safer and less-safe ways of performing it. There is apparently no need to go to the all-out Tabata protocol. Stationary cycling in sprints as short as 8 seconds 12 seconds recovery are sufficient. Raising oxygen consumption to near-maximla levels seems to be the key.
Injury through sprints on a stationary cycle seems to me less likely to generate injury than, say, 45 minutes of jogging.
Most of the actual mitochondrial assays via biopsy have indeed been performed on young, athletic males, since these represent the only group likely to volunteer for needle biopsies in exchange for a few beers.
But Trapp, et al, found major fat-burning improvements in females performing HIIT compared to similar women engaged is steady-state aerobics, with the largest effects seen in the women who were overweight. The results are in good alignment with the results seen in mean, so it seems likely that we are seeing many of the same results (lowered insulin resistance, increased mitochodial biogenesis) seen in men.
One of the other things that seems to increase mitochondrial biogenesis is resveratrol. (I was loathe to mention it, as reseveratrol has been so overhyped...)
There's a good review of mitochondrial biogenesis and aging, which includes the rather mild observation that "The complexity of mitochondrial biogenesis regulation cannot be understated..." Well, no kidding--although some of the details might be right up your alley.
If you weren't aware, retinoic acid (and probably vitamin A in general) increases CPT1 (and UCP1). Many studies show a decrease in body fat with vitamin A (and an increase in fat oxidation) and without changing plasma FFAs. I've also seen that it causes white adipose to "behave" as brown.
My coworkers, knowing my dietary habits, gave me a liver pate "cake" for my birthday today, and I noticed I became quite warm, especially my face, soon after eating it.
I suppose that mentioning trans-fatty acid as possible culprit in the mitochondria poisoning would be not too out of touch. What happens, when these unnatural fatty acids, which have physical behaviour of saturates but the instability of polyunsaturates in the organelles is probably anyones guess, but it can't be good.
I wish I could rate half of these comments. From reading these and from my own experiences, I do have some conflicting information of my own. I just want to say I'm grateful that I read up on this on my own before I read any slants.
And I'm suspicious that big pharma is behind the lack or mis-information on this topic.
There are many instances of "5 scientists and the elephant" fallacies at work here.
#1. You don't need mid-chain fatty acids. Your body naturally produces them. Anorexics have mid-chain fatty acids. Mid chian fatty acids are required for ghrelin, taking coconut oil does increase ghrelin levels.
#2. You conveniently avoided the topic of carnitine. Carnitine is necessary to metabolize long chain fatty acids. http://emedicine.medscape.com/article/942233-overview#a0104
Many insulin resistant individuals or those with endocrine issues have a carnitine deficiency.
Stargazey, i hope you're still "out there"! your blog is wonderful and we wish you'd write some more! best wishes....
Thanks, Tess! I'm afraid my brain is slowing down. I want to put only high-quality material on this blog, and I'm not sure I'm up to the challenge. We shall see, however. There is a recent article that looks very interesting, and I'm going to do my best to summarize it and put it up here. When? I don't know, but keep your fingers crossed.
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