"MC4R's job is to tell you to stop eating after a meal," says Sadaf Farooqi, professor of metabolism and medicine at Addenbrooke's Hospital. "If it's not working, you don't get that signal."
The impact on fat mass and weight of a malfunctioning MC4R are, the paper notes, detectable as early as 5 years old. By the time carriers of the same broken gene hit 18, they are 18kg heavier than those with a working MC4R.
"MC4R is the volume dial," says Professor Farooqi. "If it's not working even partially, people gain weight; if it's not working completely, people gain a lot of weight." Some of its impact, says Farooqi, is on how efficiently the body burns calories. But the vast majority of its effect is on perception. "Predominantly, it's about how much you want to eat."
That, says Dr Giles Yeo, also an author of the paper, is like a pilot having a malfunctioning altimeter. The pilot thinks and responds as if they are cruising normally at 30,000ft, when, in fact, they are dangerously close to the ground. So the person with the disrupted MC4R thinks they need to eat more, and feels hungry, when in fact their body requires no more food.
"We all have those moments when you feel hungry and wander downstairs to stare into the fridge," he says. "It's that level of hunger." Except all the time.
And though the overall weight gain is significant, he says it's easy to pile on over time. Each kilo of fat is roughly 7000 calories, so 18 extra kilos by age 18 works out at a total of 126,000 surplus calories. Eating only 10 per cent over the daily recommended adult calorie intake of 2000 calories adds up to that amount in just a couple of years.
Mutation more common than previously thought
The second major finding of the paper is that a malfunctioning MC4R is far more common than previously thought. Before, says Farooqi, researchers estimated that it might affect one in 1000 or so. Now it turns out that the figure is 1 in 337. The obesity gene is, it seems, actually quite common, carried by some 200,000 Britons.
All of which sounds like a knockout blow for the genetic determinists, and a crushing blow for the overweight fighting the flab. Both Farooqi and Yeo put the "heritability" of obesity at between 40 and 70 per cent. It can indeed feel like you are doomed to be fat.
But environment, as anyone taking a casual glance at the growing prevalence of obesity in postwar society can point out, plays a critical part.
"These genes and genetic mutations are there and have been there," says Yeo. "The change is in our environment. It's our environment that has driven this."
What he means is that there were always people who felt more hungry than others, but it is only in recent years that they have been faced with a surfeit of cheap, sugary, high-starch, high-calorie foods on which to gorge. Staring into an empty fridge, even all the time, doesn't make you fat.
Other factors, though, do. Age for one. "Age is inextricably linked to weight gain," says Yeo. Why? Lifestyle for one. "We sit on our backsides more and don't reduce the food we eat." What about metabolism, I ask, the proud owner of what I have long been told by envious chubsters must be a "fast-running metabolism" - one that keeps me ludicrously skinny even in middle age?
Both researchers are, if not sniffy, then cautious about attributing too much significance to metabolism. "Different people are more or less efficient with what they do with their food," Yeo says.
"But it's not the main driver," notes Farooqi. "Weight is ultimately about calorie intake." Metabolic effects on weight, while they exist, are "far subtler" than genetic effects, notes Yeo.
The reward system
There is, he notes, a third lever, after genes and metabolism, that the body pulls when it comes to sensing and regulating weight. It is the reward system, the "this burger tastes amazing" system, located in the aptly named "hedonic region" of the brain.
The fuller most people are, the more tempting food has to be to trigger the system. Conversely, dry bread can taste amazing if you're starved. There are individuals, they say, who take two burgers, not one, to spark that reward mechanism.
The consequences of all this are potentially catastrophic. Obesity, we have long been told, is the new smoking. Last year, for the first time, obesity was responsible for more than a million hospital admissions in England. "Covid will fade away. The obesity epidemic will not," says Yeo. "Though obesity is not what kills you - it's other related diseases."
Covid, of course, has been one of them. Epidemiologist Professor Tim Spector recently told me that 80 per cent of Covid patients in intensive care wards are obese. But that's just the start, says Yeo. "The moment obesity begins to affect human fertility - and it is, because we know obese people are less fertile - then the environment starts to kill us off, and pretty quickly."
What can you do, then, if you are the one in 337? There are existing surgical interventions that have been shown to work well, like bariatric bypasses, but there are also drug treatments currently being trialled. Some, like the diabetes drug liraglutide, have been shown to cause weight loss. Others aim to bind on to the MC4 receptor and reverse its ill-effects.
Above all, says Farooqi, what is required is more genetic testing, so that people could know if they have the mutation and respond. "The moment you have obesity as a child, it's very difficult to become unobese," says Yeo.
Genetic knowledge is power
Far from condemning carriers to despondency, say the researchers, genetic knowledge is power. "Knowing they have this gene gives people an answer," says Farooqi. "Right away, that can help with mental health and stigma."
Home DNA kits such as 23andMe are currently not targeted enough, they say. But scanning genes like MC4R for faults and correcting them at birth may become standard.
Because while the latest research seems to condemn many of us to a weighty fate, the truth is that many more of us are kept skinny by the very same gene. "If it's overactive, MC4R can protect you, give you a 50 per cent reduction in risk of obesity and diabetes," says Farooqi. And while just 0.3 per cent of us suffer the bad mutations, some six per cent of us benefit from the good.
Perhaps, in my skinny way, I sound smug. Farooqi is swift to knock me off my perch. "People who are thin and think it's easy? They're lucky," she says. That's me told.
