The answer is a quirk in part of the DNA called the ALK gene.
When the scientists removed this gene from mice, they could feed them a high-fat diet without causing the animals to pile on the pounds.
The result could lead to a slimming pill in as little as four years' time. The study's senior author, Professor Josef Penninger of the University of British Columbia in Canada, said: "We know this gene is druggable, so there could well be a pill in future which people could take to get the same effect."
Experts believe less than 1 per cent of the population has the version of the ALK gene linked to thinness. It means they have a biological difference which stops the gene working properly and may keep them slim.
After finding the gene in a database of people aged 20 to 44 in Estonia, researchers tested how it worked on mice.
They took gene-edited mice without the ALK gene and compared them to regular counterparts.
When both mice ate the same diet, those missing the gene were thinner. When the animals were fed high-fat meals, normal mice became obese, while those missing the gene stayed lean.
The study, published in the journal Cell, found mice missing the gene had smaller fat cells.
They also had higher levels of an enzyme which causes fat to be burned off quicker - as did 30 of the naturally thin people.
Knocking out the gene kick-starts a circuit in the brain which tells fat in the body to burn more calories, the authors believe.
Drugs already exist which do this, because the ALK gene is also linked to cancer.
Therefore it might be possible to develop a new drug to block the gene to help people keep weight off.
Professor Penninger said: "It's targetable. We could possibly inhibit ALK, and we actually will try to do this in the future."
