To read the previous article click here
Below is a copy of my article published in the September issue of Pampering Times.
Phil Nuttridge continues his series of articles looking at the modern take on diet and nutrition. He explodes many of the dietary myths that have defined the latter decades of the twentieth century and left their legacy of chronic illnesses in the first decades of this century. In this month’s article he looks at the evidence that calorie counting is a flawed strategy for weight loss and that it is controlled by hormones after all. More information can be found on Phil’s website cuttingcarbs.co.uk or by following him on Instagram: CuttingCarbsUK
It is incredibly difficult to make a fat mouse. If it was as difficult in humans as it is in mice, people like me would not be writing articles like this!
Although there are many ethical arguments against experimentation on animals, obesity experiments on humans are hugely problematical. So, regrettably, in order to understand better human obesity our little rodent friends are the ones under the microscope.
But there is that first significant hurdle – to study obesity in mice you have to have obese mice. And that is quite challenging. Unlike humans we can’t just give them unlimited access to convenience food, a comfy sofa and a Netflix subscription and watch the pounds pile on.
Under normal conditions (and access only to normal ‘mouse food’), laboratory mice are very good at controlling their weight. If you make excess food available to them, they just eat what they need and leave the rest. If you reduce food available to them, their metabolic rates reduce to compensate. If you dilute the energy content of the food they eat, they eat just the right extra amount to compensate. They do not need calorie counting to keep their weight in order.
Luckily for our experiments though, there are two possible ways to make a fat mouse:
- Genetic manipulation
- Addict them to sugar or foods high in synthetic fats.
Even the second of these is not a guaranteed way of making them fat as sugar-addicted obesity in mice seems to be controllable with faecal implants. I will come back to faeces later.
Taking the genetics first, there are two known variants of fat mice, named Ob and Db. Whilst both types of obese mouse look the same, the thing that sets them apart is what happens when we ‘mix’ these mice with non-obese mice. Regrettably, ‘mix’ in this context is not for the faint hearted. By ‘mixing’ I mean parabiosis, the surgical procedure whereby two mice are stitched together so that their blood circulations intermix – a bit like the opposite of separating Siamese twins. Such methods would be frowned upon nowadays, but in the Sixties when these experiments were performed, it was an accepted procedure.
Three parabiosis combinations were investigated and these are summarised below with their results:
Food was not restricted nor exercise imposed in any of these experiments – there was no enforced calorie counting. Instead, weight loss resulted from something blood-borne passing between the ‘mixed’ mice.
Where am I going with this? Well, you may remember the Swearing Gym Bunnies (SGBs) we met in my last article. We saw that they are the new breed of ‘expert’ telling us the sole reason we are fat is because we do not count our calories. The SGBs assure us that weight loss is just a simple matter of making sure you burn more calories than you eat. “Be in caloric deficit” is their mantra, i.e. eat fewer calories than you burn. Count your calories and you can count on weight loss. They assure their followers that if you do not lose weight it can only be because you are not tracking your calories properly – you are either eating more than you claim or exercising less than you claim and probably both!
The mice in our parabiosis experiments did not have SGBs shouting at them to count their calories, instead the mice lost weight because of something being transmitted in the mixed blood. It took a few decades of research to isolate what this ‘something’ was, but we now know enough of the chemistry to interpret those landmark experiments.
The Ob mouse was missing a factor in its blood that told it when to stop eating because it was full – the Ob mouse got fat because nothing was telling it when to stop eating. The normal thin mouse had this factor in its blood and so knew when it was full. When in Experiment 1 the two were mixed, the factor from the normal mouse was passed into the Ob mouse. It then had the factor telling it when to stop eating and so it lost weight.
The Db mouse’s story is a bit more interesting. It turns out this mouse not only had the ‘stop eating’ factor circulating in its blood, it actually had rather a lot of it. What had gone wrong in the Db mouse was that its brain was deaf to the ‘stop eating’ message. The bit of the mouse that produced this factor was shouting its ‘stop eating’ message ever louder but it was not being heard, hence the elevated levels of the factor. This was bad news for the normal mouse that got mixed with it in Experiment 2. The excess ‘stop eating’ factor passed into the normal mouse’s blood whose brain listened to the ‘stop eating’ signal all too clearly and kept listening. This poor thin mouse eventually died of starvation through the unrelenting ‘stop eating’ message.
In Experiment 3, the ‘stop eating’ factor from the Db mouse entered the blood of the Ob mouse, whose brain was still able to listen to the message. The Ob dramatically lost weight like the normal mouse in Experiment 2 but because it had more fat reserves, it lasted rather longer.
This factor turns out to be the hormone leptin that we met in my last article, the hormone released by the fat cells in our skin once they have received enough fat. Ob mice fail to produce leptin and Db mice produce leptin but instead their genetic fault leads to leptin resistance in the brain: No matter how much leptin you throw at it, it will not listen to the ‘stop eating’ message.
We now know that the human mechanisms controlling obesity are very similar to those in a mouse – we too have leptin. Just like the Ob mice, there is a rare genetic disorder in humans that prevents our fat cells producing leptin causing insatiable hunger and obesity. This human condition has been successfully treated with leptin injections. Humans can also suppress the production of leptin with bad dietary choices – rapid weight loss through calorie restriction being one of those bad choices. If you attempt weight reduction through eating fewer calories and those calories are high in carbs and synthetic fats, then your ‘stop eating’ signal gets quieter and quieter. You rely on willpower alone to stop eating and when that runs out, the midnight munchies kick in! Sneakily, the lower levels of leptin also slow down your metabolic processes so that the calories you expend both resting and in exercise reduce. Your balance between calories eaten and calories burnt moves away from deficit towards balance, taking you out of caloric deficit and into caloric surplus even though you continue to suppress your calorie intake. Life on reduced leptin is just not fair.
Humans can develop leptin resistance too, though unlike the Db mice in these experiments, human leptin resistance can also be developed through bad dietary choices. On the plus side, it seems that diet-induced leptin resistance in humans can be reversed at least partly.
Let’s now turn to the second way to make mice fat – sugar and faeces. Not all mice will become obese if given unlimited sugary and fatty foods but some do. It is probably of no surprise to you that sugar addiction is a contributor to obesity in mice as it is in humans but did you know mice can find sugar even more addictive than cocaine? That aside, what about the faeces?
Let me take a moment to talk about microbes. It is estimated that in a typical adult human there are around 35-40 trillion human cells. Whilst that is a very big number, what I find even more remarkable is that there are at least as many microbial cells (bacteria, fungi, virus) within each one of us too. Some estimates put the ratio of microbial cells to human cells at 3:1 or greater. Whatever the ratio, the entity that you think of as ‘you’ is at least half microbial!
Many of these microbes sit in your gut and we are now learning just how transformational they are in our relationship with food. To understand this I am afraid our rodent friends are back in the firing line.
One thing that works in our favour when we study mice is that mice will actually eat their own faeces. It even has a posh name – coprophagia. It is an evolutionary strategy that enables mice to absorb vitamin B12 and folic acid released from food by their gut bacteria but too late in the digestion process to be absorbed ‘first time around’. So, by eating their faeces, the B12 and folic acid released from the first-time processing in the gut then get absorbed in this second pass through. The consumed faeces will also contain a sample of their gut microbes. If the faeces are from another mouse, then the ingesting mouse gets exposed to the gut bacteria of the ‘donor’ mouse.
Remember I mentioned earlier that not all mice get fat when sugar is made available to them. Here’s the interesting thing: If you take the faeces from one of these thin mice and feed them to a mouse that would otherwise get fat, then the potentially fat mouse remains thin. The gut microbes of the thin mouse seem to make a pivotal difference.
Interesting corroboration of this for humans comes from the study of twins. Studying identical twins reduces the effect of genetic variation in any analysis as the siblings have an identical genetic make-up. What is useful is if you can find sets of such twins where one of the siblings is of normal weight and one is overweight or obese. Fortunately sufficient instances of such twins have been found and studied. It is particularly interesting when we look at the diversity of the gut microbes in each twin. Consistently, each normal weight twin has a much greater diversity of gut microbes than their over-weight or obese sibling.
Inconveniently (from a research perspective), we humans do not have a penchant for eating faeces! Instead, experiments of surgical faecal transplantation between thin and obese humans are showing similar results to the mice experiments.
So, what you eat matters because food groups can alter leptin production and leptin sensitivity. Your gut bacteria matter too. I think the SGBs would start swearing at me if they heard that.
Let me now anticipate an objection here: Surely it is just mind over matter – with enough willpower (being shouted at by SGBs, for example) surely we can overcome the limitations leptin imposes on calorie restriction? Fortunately there is some (old) research that helps answer that very question.
One of the big problems with human food research is the ethics of strictly controlling exactly what a group people eat and do for a sufficiently long period of time to have a meaningful and measurable effect. (Un)fortunately during the Second World War, some researchers had access to a group of people who could have their diet and exercise very rigorously controlled – imprisoned Conscientious Objectors.
Now referred to as the “1944 Minnesota Starvation study”, this experiment placed a group of Conscientious Objectors on a strict diet of reduced calories and enforced exercise. Of course, this is exactly what the SGBs tell us to do but the 1944 study enforced things to a degree no SGB could ever hope for.
In the first weeks of caloric deficit, the 1944 test subjects duly lost weight. One – nil to the SGBs. The thing is though, this weight loss did not continue as planned. The rate of weight loss reduced as the experiment progressed; even though the subjects were on the same calorie restriction and the same levels of enforced exercise – in other words, their caloric deficit was being maintained – they stopped losing weight. Some even started to regain weight.
Our calorie counting SGBs will tell us that cannot be – stay in calorie deficit and you will continue to lose weight. If the SGBs had been at the helm of this experiment they would have been shouting and swearing, claiming that the subjects were not losing weight because they were lying and cheating; they were being glutinous and/or lazy. But the Minnesota experiment showed otherwise. The subjects’ calorie intakes WERE rigorously controlled (no opportunity for cheating there) and they WERE forced to continue with the exercise regimen (no cheating there either). In fact, in order for weight loss to be achieved and maintained for the whole of the starvation phase, calorie intakes in the study were repeatedly reduced so by the end of the trial some participants were on fewer than 800 calories each day.
That this was leptin’s revenge is evidenced by the behaviour and mood of the subjects. Despite the starvation phase being conducted in the summer, the participants constantly felt cold. Their muscular strength reduced by twenty per cent. Resting heart rates plummeted, some to as low as 35 beats per minute. Cardiac outputs reduced twenty per cent; blood pressure scores lowered too. They experienced dizziness, lethargy, mania, depression, and anxiety. The lower leptin levels caused by the calorie restriction meant they were completely lethargic during the non-exercising parts of the day and burning fewer calories than before during their enforced exercise sessions. They were in such metabolic shut-down that their total calorie expenditure reduced sufficiently to compensate for the lowered calorie intake. A controlled calorie intake that had started off as caloric deficit became calorie balance, even for some caloric surplus.
When the test subjects were finally put on the recovery phase of the experiment and given freedom to eat and exercise as much or as little as they liked, the subjects dutifully and rapidly put all the weight they had lost back on and in most cases around ten per cent extra too. Their lowered metabolisms now meant that even eating food at pre-diet levels caused significant caloric surplus and therefore rapid weight gain. Their percentage body fat was also significantly higher after the experiment as their bodies had gained fat in preference to lean body mass in the recovery phase.
The Minnesota study proved that calorie deficit only works in the short term. Leave it long enough and leptin-controlled responses bring about metabolic reduction to restore caloric balance. Leptin changes also attack your mood and willpower, eventually forcing us to resume normal eating. When normal eating is restored, the reduced metabolism leads to rapid weight gain because of the now caloric surplus. The yo-yo diet is born!
To summarise, the two rules of all calorie restricted diets:
1: All diets work
2: All diets fail
Initially the diet works – better eating in terms of quantity and quality of food will give you weight loss. Eventually though the body fights back and returns you to where you started through altered metabolism and reduced willpower. Your body does not like change.
But if it does not work, why is calorie counting such a part of our psyche? Maybe it is not too dissimilar to why there are ‘flat-Earthers’ out there. Look out your window and apart from a few undulations, the Earth undeniably does look flat. However, physics and global exploration clearly show us that this is no more than a local approximation of a spherical planet. Most people accept that. If I equate ‘leptin deniers’ (a.k.a. my SGBs) to ‘flat-Earthers’, you can perhaps see my comparison. Because calorie counting works in the short term, the leptin-deniers extrapolate it as a complete long-term solution too. It is hard to convince them otherwise as, unlike a few harmless flat-Earthers, the leptin-denying SGBs make a lot of money from their view of the world!
Perhaps I can beat them at their own game. I could market a ‘STEP ON THE CRACKS IN THE PAVEMENT’ diet. It would read: “Rather than eat lunch, go outside and step on the cracks in the pavement for half an hour. Do that every day and I guarantee in two weeks you WILL have lost weight”. Ker-ching. A potential money spinner.
However, beyond this initial success, as we now know, leptin’s hold will kick-in: After two weeks, you might spend only fifteen minutes stepping on the cracks in the pavement; you might do it more slowly than at first; you might take a packet of crisps out with you while you are ‘crack-stepping’. You might dive into a mid-afternoon snack instead. You might have a power-nap in the afternoon to save some calories. Or when you get home, you are slumped on the sofa all evening rather than going to Zumba. Leptin has a lot of strategies up its sleeve. As long as I have done a runner by the time this happens and when all the weight has been put back on, I am quids-in with my cunning diet plan. And so it is for the calorie counting SGBs out there.
Leptin is inevitably just part of the story. In next month’s instalment I will share with you the story of insulin and its role in weight gain – a tale of Ice Ages, Fat Babies and Autumn binges.
To read the next article click here
Another one I’m sharing Phil.