Scientists have been trying to understand how and when we gain or lose fat cells, and now a paper in this week's issue of Nature reports that nuclear bombs are the key to solving this problem.

To understand how our bodies regulate our weight, researchers are interested in knowing how the number of fat cells changes over our lifetime - do we stop making more fat cells after adolescence? Do we keep the same fat cells all of our adult lives, or do some die off and get replaced by new ones? The typical way to study the birth and death of cells in live animals is to use radioactive tracers that label DNA, but these experiments are too toxic to try in humans. It turns out though, that the US and Soviet militaries did the experiment for us, with above-ground nuclear bomb tests in the late 1950's, tests which spewed large amounts of radioactive carbon in the atmosphere. That radioactive carbon is now in our DNA (at least for those of us alive during the cold war), and it provides a convenient "manufactured on" date for our long-lived fat cells.

Researchers from Stockholm, Berlin, and California began their work with three key questions about fat cells: How many do we have, how often are they replaced, and how does the number of fat cells change over a lifetime? Scientists have known for some time that when we gain or lose weight, we don't gain or lose any fat cells - they just change in size, gaining or losing the massive, greasy droplet of fat that sits inside of them.

The number of fat cells may stay the same, but are they the same fat cells? Or do some die off, with new ones taking their place? If some fat cells die off, and new ones take their place, then that is a process scientists would really like to know more about, to understand how the body decides how many fat cells to make.

The classical way to follow cells as they die off and new ones replace them is to use radioactive DNA. You can feed or inject lab animals with radioactive raw materials for making DNA. That DNA gets incorporated into the animals' cells, essentially putting a label on these cells that we can read with a geiger or scintillation counter. You can see how long cells stick around by giving your lab animals the radioactive food for only a short time, and then switching back to non-radioactive fare. After the switch, any new DNA made in that animal's cells will be made with non-radioactive building blocks, so by measuring how much radioactivity is left in the DNA, you determine how fast new cells are being made. In other words, we can use radiolabeled DNA to measure how fast a population of cells turns over - to determine at what rate the radioactive cells go away, and how quickly they are replaced with non-radioactive ones.

Unfortunately, we can't apply this method to humans - not surprisingly, it tends to be toxic. So how then can we measure the turnover rate of fat cells? The answer is nuclear bombs.

Early in the Cold War, the US and the USSR were testing nuclear bombs in above-ground tests open to the atmosphere. These tests polluted the atmosphere with radioactive materials, up until the Limited Test Ban Treaty of 1963, when nuclear tests moved below ground. Before the tests were moved underground, levels of radioactive carbon-14 soared:

Figure 3 from Spalding, et al. Nature 453:783-787 (2008) The relative level of carbon-14 is shown on the Y-xis of these graphs.

What this means is that the US and Soviet governments radioactively labeled the DNA of everyone then alive in the Northern Hemisphere. Plants brought that carbon-14 (C-14) from the atmosphere into the food chain, and it rapidly spread to those of us at the top of the food pyramid. After the nuclear tests were moved underground, C-14 levels dropped, mainly because the C-14 gradually was mixed around in the atmosphere and thus was diluted to almost pre-Cold War levels.

Testing nuclear bombs above ground may have been a bad idea, but it does get around the ethical issues that prevent us from injecting human subjects with radioactive substances to study their fat cells. Using the levels of C-14 in the DNA of fat cells, scientists can determine how old those fat cells are, just as if they had injected humans with radioactive tracers. Once a new cell is produced, it's largely stuck with the DNA it has at the time - if C-14 levels are high, then that cell will have DNA with high C-14 forever, as long as it's not dividing. In essence, you have a date stamp in the DNA of your fat cells that tells you 'made in 1962, when C-14 levels were X.'

In this particular study, the researchers managed to get samples of fat cells from 35 patients who had undergone liposuction. They extracted the DNA from these cells, and measured the levels of C-14 in that DNA to see when those fat cells were created. Several of their study subjects had been born well before 1955, before the bomb-induced spike in C-14. These subjects had high levels of C-14 in their fat cells, which means that these people were producing new fat cells when the nuclear tests were going on. This shows that some of these people were making new fat cells well into their early 20's.

So how late in life do people keep making new fat cells to replace ones that die off? The scientists checked the DNA of people who were born soon after C-14 levels hit their peak, beginning in the mid-1960's. In these people, who are now in their late 30's and 40's, the C-14 in their fat cell DNA was quite low - which suggests that new fat cells are being created well after the number of fat cells stabilizes (in late adolescence or early adulthood). DNA with high levels of C-14, which would been made when these subjects were growing up in the 1970's, has now been replaced with new DNA containing low levels of C-14.

Putting together all of their data, the researchers came up with a model that suggests that we replace about 9% of our fat cells each year, even after we hit that point in our lives when there is no more net gain or loss of fat cells. Using this model of fat cell replacement, together with measurements of fat cell numbers in about 700 adults, the researchers were able to draw some interesting conclusions about fat in lean and obese people, especially about the childhood roots of obesity. Obese individuals produce more fat cells during childhood, but the number of fat cells levels out early - around the age of 16 or 17. Lean individuals ultimately have fewer fat cells, but they keep producing them, at a slower rate, until the age of 18 or 19. After that time, all of us replace about 9% of our fat cells per year, but the total number remains constant.

To all of the effects of the Cold War, we can now add a giant, nuclear bomb-induced pulse-chase experiment that has helped us understand the biology of our fat cells. We all know that repetition is a key ingredient of good experimental science, but in this case, I don't think we want to repeat the experiment.