nWith apologies to James Carville (https://en.wikipedia.org/wiki/It%27s_the_economy,_stupid),we now know why it’s so hard for you to keep weight off once you’ve lost it. Your fat cells remember that they were fat once and keep acting to maintain their fatness. A great paper in Nature (vol. 636 pp. 457 – 465 ’24) did biopsies of subcutaneous fat in several people who were very overweight, before weight loss surgery and one and two years later, after they’d lost more than 25% of their body weight. They also biopsied subcutaneous fat from people who had never been overweight.
The DNA (genomes) of the very overweight people and the normal weight were different (just how the difference was manifest will be explained later).
The fascinating thing about the paper is that the DNA of the very overweight people did not change after they lost the weight. The fat cells remembered something else.
Our DNA codes for the proteins that make us up, including those involved in making and storing fat. The actual proteins involved were the same (e.g. the same amino acid sequences) in all groups, what differed was how much of them were made (and the authors showed this by actually measuring the amounts of the mRNA (messenger RNA) coding for those proteins).
The cause of the difference lies in the epigenome. Back when things were simple, the only important thing about the genome was the sequence of its 4 components, guanine, cytosine, thymine and adenine (GCTA to you). Now we know more, much more
One component of the epigenome concerns how DNA is scrunched down inside the cell nucleus. If you stretched out the DNA in each of our cells and laid it end to end, it would be about 10 feet. This does bring to mind a quote from Dorothy Parker — https://www.goodreads.com/quotes/60540-if-all-the-girls-attending-the-yale-prom-were-laid.
Cellular DNA has to be scrunched down to fit into our cellular nuclei with a length 100,000 times smaller. Depending on how much time you have you might be interested in reading a series of six posts on how this happens — start here and follow the links — https://luysii.wordpress.com/2010/03/22/the-cell-nucleus-and-its-dna-on-a-human-scale-i/
The first scrunch involves wrapping them around 8 sticklike proteins called histones. The histones can be modified in various places by adding a simple methyl (CH3 group) to them. This is one form of the epigenome (there are others). These modifications determine how easy (or hard) it is for a monster enzyme (RNA polymerase II) to ‘read’ the DNA and make messenger RNA (mRNA) which the authors measured. Here is where the epigenomes of the obese and the nonobese differ. And this is what persists even after massive weight loss (which is why we have trouble keeping it off once we lose it)
My wife’s cousin has a sign on her refrigerator
Diet: a brief period of starvation followed by a weight gain of 5 pounds
