I am a geneticist, which, last time I checked, is a perfectly upstanding profession. I mean my mother-in-law still speaks to me, so that must be a good thing, right?
And yet, when I reveal that I study the genetics of body weight and that your genetics can be the driving cause of obesity, I become a bad person. I’m perceived as giving overweight or obese people – terms I don’t use in a pejorative fashion – an excuse.
This has always been an interesting take for me. If I were studying something else, like the genetics of cancer, dementia, arthritis or any other disease, would I suddenly be giving the people who are suffering from those conditions an excuse?
I’d hope not. Instead, I hope that people would understand that I’m trying to understand biology and mechanisms, and, shocking I know, I might even be trying to help some of them.
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It's in the genes
When we talk about body weight, it’s all too often considered to be a matter of lifestyle’, a habit, a lack of willpower, a choice. The reality is that while rapid changes in our food environment and lifestyle have undoubtedly driven up the obesity figures worldwide, there are many people who are skinny and others who aren’t.
There’s clearly a large variation in body weight, even in the ‘obesogenic’ environment we live in today (one that promotes weight gain). A large part of this, although by no means all, is down to genetics.
Much of the evidence for a genetic basis to body weight has come from the study of twins. There are identical twins (who are, for all intents and purposes, genetic clones of each other) and there are non-identical twins (who share as much genetic material as you would with your own siblings or parents – 50 per cent).
If you study a large enough number of twin pairs, let’s say thousands, then you can examine any given human trait or behaviour and compare the variation if 100 per cent of genes are shared versus 50 per cent.
From these studies, we can see that the heritability of body weight is between 40 and 70 per cent. For some perspective, the heritability of height, which no one would doubt has a genetic contribution, is around 85 per cent. Body weight isn’t that far away from that.
Controlling your appetite
What we in the field now know, is that the genetics of body weight is, by definition, the genetics of how our brain influences our drive to eat. This is otherwise referred to as our appetite.
When it comes to food, appetite regulation is surprisingly complex, since it houses three broad concepts: hunger, fullness and reward. Each of these is regulated by different parts of the brain.
Hunger is regulated by a region called the hypothalamus at the base of the middle of the brain. Fullness – a feeling ranging from being comfortably content to ‘OMG, I feel like puking’ – is mediated largely by the hindbrain, the region close to where your head connects to your neck. Finally, the rewarding feeling triggered by eating is regulated by a dispersed higher brain area, loosely termed the ‘hedonic region.’
Although geographically distinct, these regions aren’t mutually exclusive of each other; they’re interconnected and speak to each other. I find it useful to conceptualise hunger, fullness and reward as three points of a triangle, with appetite sitting in the middle (accepting that this two-dimensional visualisation is a vast over-simplification).
Whenever you tug at one of the points, you’re going to affect the other two and so alter the overall shape of the triangle. A multitude of internal biological and external environmental signals influence the shape of this triangle, thus changing our overall appetitive drive.
Starting with internal signals, your brain needs two pieces of info about your status to influence appetite. First, it needs to know how much fat you’re carrying (as your long-term energy source, it’s directly related to how long you would last in the wild without food). Second, your brain needs to know how much you’re eating and have just eaten, which it gets from short-term energy signals coming from your gut.
Both these long- and short-term signals are hormonal, meaning they’re secreted into your bloodstream, where they eventually signal to the brain.
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Get a sense of your fat
With appetite regulation, the key fat-sensing circuit is the so-called ‘leptin-melanocortin pathway.’ Leptin is a hormone produced by fat, whose circulating concentrations are directly related to fat mass. In short, more fat, more leptin. This is the best-characterised and, as far as we know, the most critical circuit in the brain that senses fat and regulates appetite.
In fact, genetic mutations at every stage of this pathway result in increased food motivation and obesity.
We have, for example, found that around 0.3 per cent of the population carry mutations in the MC4R gene, which plays a part in this system. If you apply this figure to the UK population of nearly 68 million, we’re talking about more than 200,000 people. People who carry this MC4R mutation are, on average, 18kg (40lbs) heavier at 18 years of age.
This isn’t a human-specific phenomenon either; naturally occurring mutations in the melanocortin pathway have been identified in a wide range of different species.
We’ve found that 20–25 per cent of labrador retrievers, which are known to be more food-motivated than other dog breeds, carry a mutation that results in a greater appetitive drive and increased body weight. Also, certain breeds of pigs have been shown to carry MC4R mutations associated with fatness, growth and food intake traits.
These mutations even contribute to the adaptation and survival of blind Mexican cavefish to the nutrient-poor conditions of their ecosystem.
Still, for genetic disruption of the leptin-melanocortin pathway to result in severe obesity, remains a rare occurrence. The ‘common’ obesity that currently blights us is more likely to be ‘polygenic’ in origin (‘poly’ meaning ‘many’, so ‘many-genes’; this is in contrast to ‘monogenic’, or single-gene).
This will come with many subtle genetic variants, each instance of itself with an almost imperceptible effect, but when pulled together producing a cumulative measurable consequence.
There are now more than 1,000 genes that have been found to influence body mass index (BMI). Among these are genes for many components of the melanocortin pathway, including POMC and MC4R, which regulate food intake.
Humans who carry genetic variations in this key pathway, whether severe or subtle, essentially have a less sensitive fat sensor. Put simply, their brains think there’s less fat on board than they actually carry. How much less is sensed by the brain depends on the severity of the mutation. This increases the feeling of hunger, which drives them to eat more.
There’s now a drug that targets this system, called setmelanotide (from Rhythm Pharmaceuticals), which targets the MC4R to reduce hunger. It has been approved for rare genetic causes of obesity, including POMC deficiency, and is currently being trialled for those individuals with MC4R deficiency.
Repertoire of hormones
Next, we come to gut hormones. Every time we take a mouthful of food – from the moment we begin chewing until the moment it emerges out the other end – an entire repertoire of hormones is released along the way that signals to the brain not only how many calories are in the meal, but its ‘macronutrient content.’ That is how much protein, fat and carbohydrates are present.
Crucially, of the 20 gut hormones that we know exist, 18 of them make us feel fuller.
Broadly speaking, food that takes longer to digest travels further down the gut, resulting in a shift in the gut hormone repertoire, which increases fullness. This is true, for example, for foods that are higher in protein content and is one of the reasons why diets such as Atkins or Keto work – they tend to make you feel fuller, meaning you eat less and so lose weight.
One of the key gut hormones that increases substantially after a meal, and is particularly sensitive to protein, is GLP-1. The whole new class of anti-obesity drugs taking the world by storm, exemplified by the likes of Ozempic and Wegovy (both containing semaglutide), centre around modified versions of this hormone.
A main issue with native GLP-1 is its vanishingly short half-life of two minutes, as it’s rapidly degraded. These drugs’ superpower is the menagerie of chemical decorations that have been deployed to extend their life, so that current iterations have been approved as weekly injections, while others in the pipeline work as monthly injections.
As many of you would have undoubtedly experienced, when you go on a diet, you get hungry, making it difficult to sustain in the long term. What these new drugs do is make you feel full. This means that while still on the drugs, you’re able to keep the weight off without the feeling of increased hunger.
Signs in the environment
As complicated as our internal nutritional signals and their regulation are, they’re dwarfed in complexity by an almost infinite array of environmental signals. Most of these aren’t under our control, yet play a crucial role in influencing our appetite.
There are the aromas, sights and sounds of the foods themselves, such as the smells of sizzling bacon, freshly baked bread or brewed coffee; and then there are learnt cues that our primitive brains use to predict the presence of certain types of foods. Like seeing a big yellow M on a roadside sign, for instance. These signals can override any internal hormonal signals.
But the biggest environmental influence of appetitive behaviour is socioeconomic status. In the UK, those in the bottom 20 per cent of the socioeconomic strata are almost twice as likely to end up living with obesity (where the prevalence of obesity is 36 per cent) as those in the top 20 per cent (where the prevalence is 20 per cent).
In fact, in a study of twins in the Gemini cohort – a population-based prospective cohort of twins born in England and Wales between March and December 2007 – the heritability of BMI was demonstrated to be higher among those living in a lower socioeconomic and more obesogenic environment (86 per cent), as compared to those in a higher socioeconomic and less obesogenic environment (39 per cent).
The difference between rich and poor isn’t genetic, but an accident of birth.
What the study tells us is that if an individual is genetically susceptible to obesity, then being exposed to a less healthy food environment maximises their genetic burden, while conversely a healthier environment more than halves the risk. This illustrates why there is a range for the heritability of BMI of 40–70 per cent.
Primitive instincts
Ultimately, appetite is an integrated system where the triangle of hunger, fullness and reward are interconnected, while pushed and pulled by internal biological and external environmental signals. An example of this is when you’re really hungry, and simple foods taste more delicious than normal; a bit of bread, cheese or some rice is enough to trigger the reward circuits.
The fuller you are, the pickier you become, until, for example, only chocolate will do. This is the explanation for the ‘dessert stomach’ phenomenon.
Then we have the example of the role of socioeconomic status.
Basically, if your genetic hand of cards means you find it more difficult to say ‘no’ to food, then there are clear advantages to being in a situation where you’re not forced to make the decision in the first place. Compare, say, living in a leafy Cambridgeshire village, like me, versus an inner city area adjacent to a multitude of cheap and unhealthy food options.
In some quarters, there remains a strongly held belief that we’re in full control of our eating behaviour; that the environment is responsible for our shape and size, while our genes have minimal, if any, effect.
It’s crucial to remember, however, that the drive to consume food is one of the most primitive of instincts. It has been shaped by millions of years of evolution and provided living creatures with powerful and redundant mechanisms to adapt and respond to times of nutrient scarcity.
I would argue that to be overweight in today’s environment is indeed the natural (highly evolved even) response. The main issue is that this environment – where energy-dense foods and stimulatory food cues are ubiquitous, while lifestyles have concurrently changed – is in dissonance with the millennia of austere surroundings to which we have adapted.
This has pushed obesity to become the serious problem it is now.
I’m fully aware that without this obesogenic environment, most of us wouldn’t be overweight or obese. But to deny the central role that our genes have played in our response to this environment, however, is unhelpful as we strive to tackle one of the greatest public health challenges of the 21st century.
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