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!