Genetics May Affect Weight Loss

We now have three articles in three respected journals showing that weight loss over 1-2 years on a low-carb diet is equal to or better than the weight loss seen on a low-fat diet. The figure above illustrates the weight loss in the first of those three publications, the A to Z Weight Loss Diet Study.

Although the A to Z Study showed that women in the Atkins arm of the study lost the most weight on average over a year, the researchers noticed that within each diet group, the individual weight change ranged from a loss of over 30 pounds to a gain of about 10 pounds. It seemed that another factor besides low-carb helped to determine the efficiency of weight loss for particular individuals. The scientists speculated that genetic differences might be at work.


Genetic Test
The first discussion of the interaction of genes and the A to Z Weight Loss Diet showed up in a lifestyle article in the Wall Street Journal. The article described how Mindy Dopler Nelson and Christopher Gardner attempted to contact the 301 women in the original A to Z study and found about 140 who were willing to submit DNA by means of a cheek swab. The swabs were sent off to Interleukin Genetics and were analyzed for three genes that had been shown to have some relationship to body weight in at least three clinical studies.

The Interleukin Genetics site has a summary describing the science behind its weight management genetic tests. Briefly, the panel involves five variations in four genes. These involve single nucleotide polymorphisms (SNPs) that subtly change proteins involved in body weight by changing one of the amino acids in the protein sequence in question. Proteins, as you will recall, are linear strings of amino acids. The particular sequence and identity of the amino acids determines how the protein folds and how it interacts with other molecules within the body. Change one of the amino acids and you'll modify the way the protein works.


FABP2
The first protein tested in the panel is fatty acid binding protein 2, or FABP2. FABP2 is a protein found in epithelial cells of the small intestine, and it influences fat absorption. When the alanine at position 54 of FABP2 is substituted with a threonine, this causes increased absorption of dietary fatty acids by the intestine. (The specific scientific references for these claims and the ones for the other genes listed below can be found in the Interleukin summary publication linked above.)


PPARG
The peroxisome proliferator-activated receptor-gamma (PPARG) protein is expressed in fat cells and plays a role in adipogenesis. When there is a proline at position 12 of the protein, the person carrying that gene variant will find it easier to gain weight as a result of fat in the diet. By contrast, people with an alanine at position 12 of the PPARG protein will tend to lose weight more easily.


BAR2
The beta-2 adrenergic receptor (BAR2) gene is involved in mobilization of fat from adipocytes in response to hormones like epinephrine and dopamine. There are two important polymorphisms of BAR2, one at positon 27 and another at position 16.

Women with glutamine at position 27 show no risk of obesity on a high carbohydrate diet, while women with a glycine at that position showed an increased risk of obesity when they adhered to a high carbohydrate diet.

Individuals who carry a glycine at position 16 of the BAR2 protein are at higher risk of weight gain over their lifetimes than those who carry an arginine at that position. Glycine-16 individuals are also less likely to lose weight in response to an exercise program.


BAR3
Another type of beta adrenergic receptor, BAR3, is found in visceral adipose tissue and is involved in regulation of lipolysis, that is, the breakdown of fat. This gene was not considered in the reanalysis of the A to Z Diet Study, but it is interesting nonetheless. People with an arginine at position 64 of the BAR3 protein found it much easier to lose weight in response to exercise than those who carried a tryptophan at position 64. This variation may help explain why some people swear that they can lose weight by exercising, while others swear that exercise makes no difference to their weight loss.


A to Z Reanalysis
When the group at Stanford learned the results of these tests, they were able to group the women in their study into low-carb genotypes and low-fat genotypes. Unfortunately, since we only have press releases to guide us, the specific criteria for the genotypes is unavailable. They did say that when women with the low-fat genotype were on the very-low-fat Ornish diet, they lost an average of 14.1 pounds, while those with that genotype who were on the relatively high-fat Atkins diet averaged a loss of only 2.2 pounds. Women with the low-carb genotype lost an average of 12.3 pounds on the Atkins diet and 3.1 pounds on the Ornish diet.

This study has not yet been published in a peer-reviewed journal, but the findings are interesting nonetheless. It is fascinating to speculate that low-carb and low-fat diet and exercise plans might produce better or worse results depending upon our genes. At the same time it's important to remember that the A to Z participants were premenopausal, non-diabetic white females. Even if the findings of the Stanford group prove significant, it is impossible to tell how they will apply to older people, to diabetics, to nonwhite populations and to men. There are, however, 44 studies cited at the end of the Interleukin Genetics summary article, and these do address the function of the four target genes in many types of patient populations.

If you have $149.00 in extra cash, you might even want to take the test and see if the results comport with your experiences in various weight loss approaches. I have no financial interest in Interleukin Genetics, but would be very interested to see if there is any validity to using genetics as a strategy to assist in weight loss.

Low-Carb versus Low-Fat

Ladies and gentlemen of the low-carb community: We have a hat-trick.

1. On March 7, 2007, the Journal of the American Medical Association (JAMA) published an article showing that, at 12 months, women assigned to the Atkins (low-carbohydrate) diet lost more weight and experienced more favorable metabolic effects than did women assigned to follow the LEARN, Ornish or Zone diets.

2. On July 17, 2008, the New England Journal of Medicine published an article describing a two-year study of men and women in Israel. The study showed that, compared with the low-fat diet, the low-carbohyrate diet produced greater weight loss and had more favorable effects on lipids. The authors concluded that low-carbohydrate diets may be an effective alternative to low-fat diets.

3. And finally on August 3, 2010, the Annals of Internal Medicine published an article describing a two-year low-carb vs. low-fat study of men and women in the United States. The authors concluded that, "Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years."

Three refereed articles in three well-respected journals. Although the second study had some funding from the Dr. Robert C. and Veronica Atkins Research Foundation and might be faulted for that reason, the first and third were supported by the National Institutes of Health (NIH). All three studies showed that a low-carbohydrate is effective for weight loss. All three showed that metabolic effects, including an increase in HDL cholesterol, improved with the low-carbohydrate diet. And while the first study lasted a year, the last two studies covered a two-year span, demonstrating that the benefits of a low-carb lifestyle are not limited to a few weeks or months.

Currently the third article is only available for free in abstract form. However, Jimmy Moore purchased the article and did an excellent summary which can be found here. I purchased the article, too, and found that most of my observations agreed with Jimmy's, so I'll refer you over there if you would like a thorough discussion of what the article showed. [Great news! Thanks to LynMarie Daye in the Comments, we now have a link to a free PDF of the entire article: Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet.]

I'll just emphasize a few points.

First of all, the people in the third study lost an average of 11 kilograms at six months, while the average six-month loss for low-carbers in the first two studies was about 6 kilograms. That's probably because the average BMI in the third study was about 36, vs. about 31 in the other two studies. As a general rule, the more a person weighs, the easier it is to lose a given amount of weight.

Second, in the Annals of Internal Medicine study, the low-carb dieters lost (and regained) almost exactly the same amounts of weight as did the low-fat dieters. This may be because both groups received regular instructional sessions lasting from 75 to 90 minuntes throughout the two years of the study. Or it may be because the low-carb group was treated differently from the low-fat group. The low-carb group began the study at 20 grams of carbs per day, but at three months they were raised 5 grams of carbs per week until they reached a level of carbs at which they could maintain their weight. The low-fat group began the study eating 1200 to 1800 calories per day with less than 30% of their calories from fat, but they were never transitioned to a maintenance level of calories per day. In contrast with the low-carb group, at the end of the study the prescribed regimen for the low-fat group had not changed. It is hard to know how much additional weight the low-carb participants would have lost if they had been allowed to transition to their Critical Carbohydrate Level for Losing (i.e. the number of carbs that would allow them to continue losing 1-2 pounds per week) rather than being moved directly to a maintenance program.

Third, the weight loss in the low-carb group was not a loss of water weight. Both groups experienced similar reductions in lean mass (about 5%) and in fat mass (11% to 20%).

Fourth, in all three studies, the LDL cholesterol increased for the low-carb groups at three to six months, but was at or below baseline by the end of the study. Why this happens is not clear, but it seems to be a common finding when people begin a low-carb diet. Unfortunately none of the three studies measured LDL particle size, an important factor because small, dense LDL particles are more atherogenic than large, fluffy LDL particles. And people with higher HDL, as was seen in the low-carb group, tend to have the large, fluffy form of LDL cholesterol.

Fifth, an interesting aspect of the Annals of Internal Medicine study was the fact that it addressed the issue of dieting and bone loss. Both the low-carb and low-fat groups lost 1.5% or less of their bone mineral density during the course of the study. A small loss is unsurprising because the bones of both groups had less weight to carry as the study went on. However, there was no between-group difference in loss of bone mineral density in either the hip or the lumbar spine. There are blogs all over the internet suggesting that the relatively high protein intake of a low-carb diet causes calcium to be leached from bones and results in osteoporosis. The theoretical basis of this idea is shaky at best, and in a practical sense the Annals of Internal Medicine study indicates that this type of fear mongering is unfounded.

To sum it up, low-carbers now have solid scientific evidence that low-carb works for weight loss and that it improves metabolic health markers as well. If your doctor objects to your practice of the low-carb lifestyle, you might want to print out these three articles, read them, and take them along to your next office visit. For those who are skeptical about the benefits of low-carb, the positive scientific evidence is only getting stronger.