FTO, cohort of birth and body mass index

In a recently accepted article in PNAS, entitled "Cohort of birth modifies the association between FTO genotype and BMI," the association of FTO variant rs993609 with body mass index is described as having essentially zero influence for study participants born before 1942 and increasing influence on this obesity phenotype as participants were born in increasingly more recent years. That long-range enhancers within the FTO region recapitulate aspects of IRX3 expression implies that the obesity-associated interval serves to regulate IRX3. Consistent with this, obesity-associated SNPs are associated with expression of IRX3, but not FTO, in human brains. Nonetheless, this is an important obesity locus, be it FTO or IRX3 as the functional unit. 
 
The authors rightly suggest that gene-environment interactions (GxEs) coupled with changes to the environment of the participants could alter the FTO-BMI association. 

FTO is subject to exercise-induced changes in DNA methylation. See, for example, table 5 (and reference 3) of  Rönn, Volkov, et al. We have cataloged a large number of genetic variants that show the type of GxEs suggested by the recent PNAS article. That catalog shows that some nine different studies observed modulating effects of physical activity on the FTO-BMI association. (In most populations of European ancestry, for example, in which many of these studies were conducted, the variants analyzed are in relatively strong to very strong linkage disequilibrium.) Other lifestyle choices also modulated the effects of FTO variants, including macronutrient intakes of carbohydrate, and fatty acids such as saturated fat, MUFA (mono-unsaturated fatty acid) and PUFAs (poly-unsaturated fatty acids). Whether time spent engaged in physical activity shrank as the birth cohorts became more recent, or diet changed, or some combination of this, is difficult to ascertain. But a list of known FTO-BMI GxEs would be a good place to begin such an analysis.
 

Life aboard the International Space Station

As some of you who follow me on Twitter may already know, NASA astronaut Suni Williams and I were childhood friends. We were on the same swim team together. She is aboard the International Space Station (ISS) at this moment on Expedition 32, beginning a 4-month stay about a week and a half ago. Since her first trip to the ISS in 2006, I've been in touch with her and that got me on the invite list to attend a special launch party for her current mission. At that event, there was a special presentation by Captain Dan Burbank. He was Commander of Expedition 30 to the ISS and returned to Earth on 27 April 2012 after a five-month stay aboard the ISS.

I was curious to learn about the behavior of the astronauts on the ISS in terms of diet, physical activity (especially with regard to bone loss and muscle function) and sleep. Many of you know how our research group examines the role of environmental factors in modifying disease risk. These are GxE, or gene-by-environment, interactions. Diet, dietary components (eg, certain fatty acids, protein content, carbohydrates), exercise (or sedentary behavior) and sleep are key environmental factors for our work.

Dan told me that he would normally consume about 3500 calories per day on Earth but that increased by about 500 calories aboard the ISS. He could not say if it was more carbs or fat or protein or just a bit more of everything. He did not speak much about exercise other than to tell us all during his slide presentation that there is a new resistance machine on board that provides 400 pounds of resistance. The previous machine provided only 100 pounds of resistance and the 400 level is what is needed to stem bone loss. He told us that when one types on a keyboard, only a few strokes are needed to send the person across the room in microgravity. So, they "stand" with feet hooked under railings, like as bar rail. This gives them calluses on the tops of their feet, while those on the soles begin to fade.

What was perhaps the most interesting to me was Captain Dan's sleep habits. He said that on the ISS he needed only 4 to 7 hours of sleep per night. What's more, he did not strap himself in to provide a feeling of lying down, but could sleep anywhere, floating in his room.

All in all, it was a really cool experience to meet an astronaut, to learn about life aboard the ISS, and to see someone I know launch with a Soyuz rocket to begin her latest adventure.

Good luck and continued success with your mission, Suni!

POTW: Exercise and gene methylation

The Paper of the Week for 9 March 2012 was entitled "Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle" by Barres, et al. It appeared in Cell Metabolism as a Short Article.

The exercise test was performed on a stationary bicycle. One cohort of subjects were exercised until reaching either 40% or 80% of VO₂ peak. A second cohort was exercised until 1,674 kJ were expended. These were acute interventions, making the findings all the more remarkable.

I found the following to be key points of this paper:

1. In both healthy, sedentary women and men, it was observed that whole genome methylation was decreased in skeletal muscle.

2. While exercise induced expression of PPARGC1A (PGC-1α), PDK4, and PPARD, the authors also noted reduced methylation at each of the promoters for these genes.

PPARGC1A is a key transcriptional regulator of OXPHOS (oxidative phosphorylation) genes. It is also an important type 2 diabetes gene.

Optimal values

If a little of this or that is good, then more must be better for me, right? No, but unfortunately, many of us think this way. Still others with some knowledge of how things are in a biological or physiological or medical context understand that a plateau of effect is often reached whereby a given compound or nutrient is no longer effective. But often ignored is the adverse effect of taking in too much of that substance. Hence, there is an inverse bell curve, as shown below, that most probably explains the effects of most substances we each encounter whether at the dining table or elsewhere in the environment.

Allow me to provide a short example. Athletes who take oxygen from the sidelines ostensibly to "recover." A higher intake of oxygen will actually saturate the hemoglobin in the red blood cells and hinder exchange of carbon dioxide transfer from peripheral tissues. Sure, breathing pure oxygen reduces respiration rate - less huffing and puffing after scoring that touchdown - but has little value in allowing the muscles to recover.

Thus, as has been so often said - everything in moderation.