Sunday, January 10, 2016

Think Tank #2: Fat Cell Turnover in Humans

Science Blogs:
As fat people have an abundance of fat tissue, the natural assumption is that fat people have more fat cells, or ‘adipocytes‘. That’s only part of the story – it turns out that overweight and obese people not only have a surplus of fat cells, they have larger ones too.

The idea of these ‘fatter fat cells’ has been around since the 1970s. But their importance has been dramatically highlighted by a new study, which shows that the number of fat cells in both thin and obese people is more or less set during childhood and adolescence. During adulthood, about 8% of fat cells die every year only to be replaced by new ones. As a result, adults have a constant number of fat cells, even those who lose masses of weight. Instead, it’s changes in the volume of fat cells that causes body weight to rise and fall.

Kirsty Spalding from the Karolinska Institute in Sweden, together with a large team of international researchers, uncovered several lines of evidence to support these conclusions. Her study is a fascinating mix of cell counting, stomach surgery, radioactive Cold War fallout and a rather surprising use for carbon-dating.

First, off she compared body fat measurements from over 800 people to the size of their fat cells, as viewed under a microscope. She found that people with more body fat also had larger fat cells and this held true for fat deposited both under the skin (subcutaneous) and around the belly (visceral). However, body fat and fat cell volume weren’t perfectly matched – the number of fat cells was also important.

Spalding counted the total number of fat cells in 687 adults and combined these tallies with measurements for children and adolescents taken from previous studies. Together, the data showed that a person’s pool of adipocytes is set during childhood and adolescence, increasing during these periods and levelling off during adulthood. Both lean and obese people showed the same pattern and adults in both categories had very little variation in their fat cell count.

Even people who lost massive amounts of weight still had the same number of fat cells. Spalding studied the fatty tissue of 20 people before and after they went through bariatric surgery, a set of drastic procedures that shrink the stomach with staples and bands, or bypass it altogether. It’s an extreme approach to weight loss, but it works, and the people in the study dropped an average of 18 BMI points. Even so, they still had the same number of fat cells a year or so after the operation! The fat cells had however shrunk by about a third (see below).

Carbon-dating fat
An unchanging number of fat cells means one of two things – the same cells persist throughout adulthood, or they are destroyed and replenished at the same rate. Spalding suspected the latter, and to prove it, she relied on the most improbable of sources – fallout from the Cold War.

During the late 1950s, the world’s superpowers busied themselves by testing their new nuclear arsenals, unleashing a large amount of radioactive isotopes which spread around the globe. These included 14C, a form of carbon typically found at low background levels in the atmosphere. From 1955, atmospheric levels of 14C shot up to heights unheard of for thousands of years, only to fall exponentially after the Test Ban Treaty of 1963.

In the meantime, the extra 14C was converted into carbon dioxide, taken in by plants, and made its way up the food chain. Some of it ended up in the bodies of people alive at the time, and if any of them were creating new fat cells, these would be laced with unusually high levels of 14C. In this way, the levels of 14C in any adipocyte acts as a time stamp, directly reflecting the amount in the air at the time it was created.

The bomb tests had inadvertently given Spalding a way of carbon-dating fat. And she could do so very accurately, because of the massive year-on-year changes in atmospheric 14C (I blogged about the same technique a couple of years ago, when it was first used to study the creation of neurons in the adult brain).

She took fat tissue from 35 people who were either lean or obese and used them to create cultures of fat cells that were almost completely pure. That’s important as contamination with other cell types that turn over at different rates would have messed up the results.

She found that all the samples taken from people born before 1955 had levels of 14C that were substantially higher than the low atmospheric levels before the bomb tests. People born after the Cold War showed the tests showed the same pattern – their fat cells were often about 20 years or so younger than they were. These cells were clearly produced during either adolescence or adulthood.

Life and death of fat cells
Armed with all of this data, Spalding managed to model the life and death of fat cells. She discovered that obese adults produce about twice as many new fat cells every year as lean ones. However, obese adults also have more fat cells anyway than lean ones, and the proportion of new cells added is the same in both groups. These similar birth rates are matched by similar death rates, so regardless of weight, adults replace about 8% of their fat cells every year. In early life, things are different. Compared to their lean peers, obese children add new fat cells at twice the rate, which is why they end up with a bigger complement of fat cells..

Spalding’s stunning results help to explain why so many overweight and obese people find it very hard to lose weight. Having built up a large supply of fat cells that is constantly replenished throughout adult life, they’re already at a disadvantage. Previous studies have shown that an overabundance of fat cells leads to a deficiency of leptin, a hormone that normally keeps appetites in check and boosts metabolism. With leptin in short supply, people eat more and their numerous fat cells become swollen with extra lipids.

There is one caveat – the obese people included in the study were all obese from an early age. So it’s unclear if the fat cells of people who gradually gain weight during adulthood will eventually reach some maximum size and trigger an increased production rate for new cells. It’s a possibility, but it’s unlikely to be a very important one because surprisingly few people become obese as adults. While 75% of obese children grow up to be obese adults, only 10% of those with a healthy weight do the same.

Drugs, policies and stigmas
Spalding also suggests that her discoveries could be used to develop innovative treatments for obesity. Some cell types are subject to simple feedback loops that limit their number. Muscle cells, for example, secrete a molecule called myostatin that in sufficient quantities, blocks the production of new muscle cells. It’s likely that fat cells operate under the watch of a similar cellular thermostat and the molecules involved, if we can identify them, would make enticing targets for anti-obesity drugs.

Such development are likely to be years away, and for now, the rising levels of obesity around the world pose a more immediate problem. In this study, we couldn’t have a clearer indication of the importance of childhood as a window for preventing obesity and the chronic diseases affected by it – cancer, heart disease, diabetes and more.

The message is especially stark following the recent Foresight report, which estimated that if current trends are left unchecked, by 2050 a quarter of all UK children under the age of 16 will be obese. The knowledge that their fat cell count will then be set for life makes the cost of inaction even higher. Fortunately, it seems that the UK Government is taking appropriate steps and recently pledged over a third of a billion pounds on a concerted strategy to tackle childhood obesity.

The study doesn’t just affect how we deal with obesity pharmaceutically and politically, but socially as well. The more we learn about obesity, the more ludicrous it becomes to blame the condition on a lack of discipline or shoddy willpower. It’s clear from studies like these, and our ever-increasing understanding of the genetics of obesity, that being fat has a strong biological basis that can be very difficult to overcome.

Images: All graphs by Nature; belly by Thomas

Reference: Spalding, K.L., Arner, E., Westermark, P.O., Bernard, S., Buchholz, B.A., Bergmann, O., Blomqvist, L., Hoffstedt, J., Näslund, E., Britton, T., Concha, H., Hassan, M., Rydén, M., Frisén, J., Arner, P. (2008). Dynamics of fat cell turnover in humans. Nature DOI: 10.1038/nature06902

1 comment:

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