Input - Output = Net Accumulation
Thus eat too much means you get fat. Of course the problem with the above is; how does one measure input and output. The classic manner is in food and Kcal. Thus:
3500 Kcal = 1 pound
That is for every 3500 Kcal one consumes above a Basal Metabolism burn rate one gains a pound.
However not all food is equal and not all people burn calories at the same rate. Thus perhaps there is a genetic factor on burn rates. That does not negate the above argument.
Into this fray is a new article in NEJM. They state:
Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects.
This is 3 genes and a single SNV. But we must always ask; what is the cause? Again it appears that with these genes fat cells burn at a lower rate. Thus if a normal person, whatever that means, can deal with 1800 Kcal per day and not gain weight then a gene encumbered person may only burn 1200 Kcal per day and eating the same amount will thus gain weight. So eat less! The cause of obesity is consumption. If one has a lower set point then eat less.
Now in the MIT write up of this article the authors state:
But there may now be a new approach to prevent and even cure obesity, thanks to a study led by researchers at MIT and Harvard Medical School and published today in the New England Journal of Medicine. By analyzing the cellular circuitry underlying the strongest genetic association with obesity, the researchers have unveiled a new pathway that controls human metabolism by prompting our adipocytes, or fat cells, to store fat or burn it away. “Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism,” says senior author Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute.
Well frankly the CSAIL reference is wrong. It does not relate to exercise bu cell burn rates. We always knew that. We further know that some people's cells burn at different rates and that obese people burn at a lower rate. The classic case is the Southwest Indian Tribes who most likely after generations have adapted to low caloric input due to the nature of their environment and thus have a lower conserving burn rate. We see this in many immigrants from countries where food was no readily available. The Irish and many Hispanics have a similar characteristic. (Also some early epigenetic studies demonstrated inheritable traits from WW II starvation in the Low Countries).They can maintain lower weight by not eating our high calorie foods. Don't blame the genes, in fact the genes have adapted to the harsh limited food environment which may be beneficial.
The NEJM article concludes:
Last, we found that direct manipulation of the ARID5B–rs1421085–IRX3/IRX5 regulatory axis in primary cell cultures of adipocytes from patients reversed the signatures of obesity. This indicates that in addition to changes in physical activity and nutrition, manipulation of mitochondrial thermogenesis offers a potential third pathway for shifting between energy storage and expenditure in a brain-independent and tissue-autonomous way in humans. In summary, our work elucidates a mechanistic basis for the strongest genetic association with obesity. Our results indicate that the SNV rs1421085 underlies the genetic association between the FTO locus and obesity. The SNV disrupts an evolutionarily conserved motif for the ARID5B repressor, which leads to loss of binding, derepression of a potent preadipocyte superenhancer, and activation of downstream targets IRX3 and IRX5 during early differentiation of mesenchymal progenitors into adipocyte subtypes. This results in a cell-autonomous shift from white adipocyte browning to lipid-storage gene expression programs and to repression of basal mitochondrial respiration, a decrease in thermogenesis in response to stimulus, and an increase in adipocyte size. Manipulation of the uncovered pathway, including knockdown or overexpression of the upstream regulator ARID5B, genome editing of the predicted causal variant rs1421085, and knockdown or overexpression of target genes IRX3 and IRX5, had a significant effect on obesity phenotypes.
Now the last things we need is a new medication to control genetic pathways when the answer is just lower food consumption. That is free!
As an aside I found that the paper relied on murine samples. In addition they state:
To translate the results of genomewide association studies into mechanistic insights, we combined public resources (epigenomic annotations, chromosome conformation, and regulatory motif conservation), targeted experiments for risk and nonrisk haplotypes (enhancer tiling, gene expression, and cellular profiling), and directed perturbations in human primary cells and mouse models (regulator–target knockdown and overexpression and CRISPR–Cas9 genome editing).
Let's just hope we don't do CRISPR Cas9 editing on humans for obesity! Just a concern.
Oh and by the way, there is a very effective tool already in use. It is called the Scale. Cheap, lots of them around, and it provides a set point feedback loop. You get on it once a day and if it gets higher you stop eating, if it gets too low, then see a Doc!
And yes, one last thing, the MIT Stata Center where CSAIL is located has a "food court" I used to frequent, albeit carefully. The food there is carb rich, and more than likely will be the cause of later obesity issues. So one must always examine their own sand box, and not blame the genes for everything!
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