It has recently been discovered that gene editing can transform the fat that we store in our bodies from white fat to brown or beige fat. Most of the fat we store is white fat and its function is simply to store energy whereas brown/beige burns energy.
This week I am writing about body fat and how white fat can be turned into brown fats which burns energy instead of storing it. I have had reason to be grateful in the last few weeks because I now have the wonderful Helen proofreading my articles and she deserves a shout out! Although this might seem a little strange for her as she will be proofreading something that mentions proofreading three times in the opening two sentences! Just to make sure she is paying attention. Are we not pure? “No, sir!” Panama’s moody Noriega brags. “It is garbage!” Irony dooms a man—a prisoner up to new era. That was intentional Helen as it an example of a palindrome , which is a word or sentence that is the same back to front!
There have been huge swings in almost all aspects of our lives this year. This is also true meteorologically. It is a peculiar observation that each lockdown directly proceeded the wettest months on record. We have just had the highest monthly total of recorded rainfall in October since records began. Data collected in October in Oxford at the Radcliffe Observatory measured 185.3 mm of rain, the highest monthly total since it started recording in 1875.
We also had a record 27 rainy days in October (≥ 0.2mm/day) and October 3rd was the wettest day on record with an average of 31.7mm across the entire UK in the aftermath of Storm Alex (equivalent to a staggering 7.4-7.5 cubic kilometres of water). Just imagine how miserable that would have been had we have been in lockdown then. Small mercies. Weirdly February this year was also the wettest on record in the aftermath of Storms Ciara and Dennis before we went into lockdown in March.
My last piece before half-term described the achievements of Emmanuelle Charpentier and Jennifer Doudna who were awarded the Nobel Prize for Chemistry. Their pioneering work led to development of a technique called CRISPR (pronounced ‘crisper’) which stands for ‘clustered regularly interspaced short palindromic repeats.’ Their ground-breaking discoveries allow us to undertake gene editing and it has many potential applications beyond changing the colour of our dairy cows in New Zealand.
Gene Editing Can Turn White Fat into Brown Fat
It has recently been discovered that gene editing can transform the fat that we store in our bodies from white fat to brown or beige fat. Most of the fat we store is white fat and its function is simply to store energy whereas brown/beige fat challenges our assumption of fat as it does the opposite and burns energy. But now genes have been identified that order fat cells to burn energy rather than store it, raising the prospect of a gene therapy to treat obesity.
As most of us know as soon as our body digests protein, fat, or carbohydrate, it turns them into amino acids, fatty acids, or glucose, respectively. Fundamentally we convert fat into fatty acids, which is either utilised immediately or is directly stored in various parts of our bodies like hip, thighs and in the abdominal areas. Glucose from carbohydrates and protein is stored in the same way with help from the hormone insulin.
There are twenty different types of amino acids derived from proteins and all of these except two (leucine and glycine) can be converted into glucose. Obviously, this storage process occurs when we consume too many calories. In general, the storage of fat is an issue in terms of metabolic risk when it is stored in the abdominal area but not when it is stored around the hips and thighs.
Unfortunately, in the UK our obesity crisis is such that we are now the most obese nation in Western Europe! The latest annual report published by the NHS in May called “Statistics on Obesity, Physical Activity and Diet 2019” outlines some alarming facts. Data from the report showed that 29 per cent of adults are now obese and more than a fifth of men and women are physically inactive.
Similarly, only 20 per cent of boys and 14 per cent of girls meet the Government’s guidelines for an hour’s exercise a day. Any solutions that may help with our expanding waistlines can only be a good thing. This raises the question of whether activation and recruitment of brown or beige adipose tissue can be used to counterbalance the current obesity pandemic. Before we move on to possible solutions it is important to understand the role of brown and beige fat.
Brown Fat is a Recent Discovery
Brown and beige fat unlike white fat burns energy. A white fat cell (or adipocyte) has one single large fat (or lipid) droplet, and this characterises its colour, so it is known as white or yellow fat. Brown adipocytes on the other hand contain many small lipid droplets which also happen to have high number of iron-containing mitochondria. Indeed, it is this high iron content that gives brown fat its dark red colour.
These mitochondria are slightly different from those in other cells, too, because they contain a protein called thermogenin, or UCP1, which enables brown fat to turn energy to heat directly. Brown fat also has many more tiny capillaries (blood vessels) because the mitochondria have a high rate of oxygen consumption. Brown fat typically builds up in quite different anatomical locations than white fat. It mainly accumulates around our neck anatomy and spinal cord.
Brown fat has long been an enigma. Evidence of its very existence comes from an intriguing study conducted by the US army 60 years ago, when they subjected 10 men to temperatures of 11 °C, for 8 hours a day for a month. These days they may have had problems with the Ethics Committee! Electrodes on their skin showed that their shivering decreased after two weeks, suggesting that their bodies had somehow adapted to the cold.
The team concluded that some form of metabolic process was involved although it remained a mystery. This famous study was recreated in 2012 at Maastricht University in the Netherlands. In this study they used positron-emission tomography (PET) scans and fat and muscle biopsies to measure brown fat activity, as well as monitoring shivering. Remarkably after 10 days, brown fat activity had increased, and the subjects could generate the heat they required without shivering.
Brown adipose is especially useful if the body requires the generation of extra heat (thermogenesis). This is important for several reasons. Good examples are if we have a temperature (or fever) in response to an infection or are subjected to cold temperatures (hypothermia) or also for some mammals that need to increase body temperature when they come out of hibernation. New-born babies are very susceptible to hypothermia particularly if they are premature as they lack brown adipose tissue. Full term babies contrastingly do not shiver as they have much higher levels of brown adipose tissue (5% of total body weight) although this declines with age.
The problem with brown fat is that we do not have much of it and what we do have decreases with age. However, in 2012 at the Harvard Medical School there was another type of fat that was discovered and this was beige fat. Beige fat is found in different anatomical areas to brown fat and is much more abundant. It is found interspersed in white adipose tissue, but it crucially contains the same protein, UCP1, which burns calories to generate heat. Beige fat could be an ideal target to help control weight.
Studies Surrounding Changing White Fat Cells into Brown Fat or Beige Fat
A study was done in 2016 that implanted beige adipose tissue cells in mice (it is those poor little mice yet again!). These mice were fed a high fat diet (not pizza and KFC!) in the name of research. It is worth mentioning that there are strict protocols in place to ensure the welfare of the mice. All animal use in this study was in accordance with the guidelines of the Animal Care and Use Committee of the University of Massachusetts Medical School.
What was remarkable in this study is that beige adipose tissue helped the mice metabolise and burn fatty acids. The implantation significantly helped with glucose homeostasis and allowed them to regulate the blood sugar levels much more effectively. So, there is a clue in there somewhere and it certainly appears that beige adipose can help maintain a healthy bodyweight.
Genetics of course also have a role in obesity. The FTO gene was discovered in 2007 and half the population in the UK carry a variant which will make then 1.6kg heavier than the rest of the population. Also 16% of the population carry two copies of the variant FTO gene which will make them on average 3 kg heavier. As it turns out this faulty FTO gene stops the development of beige fat.
It has been discovered that the FTO gene variant activates two other genes – called IRX3 and IRX5 – which then direct white adipose tissue to store energy. The FTO gene makes IRX genes twice as active in white fat adipose tissue in people that carry the variant gene essentially making them super-storers of energy.
In cells from people with the normal FTO variant, the same two genes are switched off and this causes the cells to burn energy instead. A research team from Harvard Medical School were able to use gene editing techniques (CRISPR) to adjust the functioning of the FTO gene in fat cells, converting fat-storing cells into fat-burning cells. They deactivated the IRX3 gene in mice (sorry mice !) fed a high-fat diet (more pizzas!) and animals resisted piling on the pounds. Unfortunately, the little mice with the IRX3 gene activated gained an extra 15 per cent of their body weight.
In 2017/18, approximately 711,000 hospital admissions in England had obesity recorded as the first or second reason for admission, up from 617,000 the year before. These figures imply a 15 per cent increase in the number of hospital admissions where obesity is the main or secondary reason. The point is we are not getting any thinner! Hopefully this avenue of scientific enquiry will bear fruit in the none-too-distant future.
