A common variation in the FTO gene affects one in six of the population, making them 70% more likely to become obese - but until now experts did not know why.
Using a series of tests, a British-led research team said they had found that people with the variation not only had higher levels of the "hunger hormone" ghrelin in their blood but also increased sensitivity to the chemical in their brains.
"It's a double hit," said Rachel Batterham from University College London, who led the study, which was published in the Journal of Clinical Investigation on Monday.
The discovery follows studies of blood samples from people after meals, combined with functional magnetic resonance imaging of volunteers' brains and cell-based studies looking at ghrelin production at a molecular level.
Batterham said the work provided new insights and possible new leads for treatment, since some experimental drugs are known to suppress ghrelin and could be particularly effective if targeted at patients with the obesity-risk variant of the gene.
Previous research has also shown that ghrelin can be reduced by eating a high-protein diet.
Steve Bloom of Imperial College London, who was not involved in the study, said the FTO gene only explained a small part of the obesity epidemic but the latest discovery was "an important step forward" in unravelling the various factors involved.
Statistics show alarming numbers
The prevalence of obesity is increasing worldwide at an alarming rate and both developed and developing countries are affected. Obesity is a major risk factor for diabetes, heart disease and certain cancers.
At least 2.8 million adults die each year as a result of being overweight or obese and more than 40 million children under the age of five were overweight in 2011, according to the World Health Organisation.
Developing effective obesity drugs has been a challenge for drugmakers, although some new medicines are now coming through.
Obesity drugs still being worked on
After a gap of more than a decade, two new obesity drugs - Vivus Inc's Qsymia and Arena Pharmaceuticals Inc's Belviq - were approved by the US Food and Drug Administration last year.
Belviq's launch was delayed, however, pending a final classification on its risk of abuse and Qsymia's sales have been disappointing, triggering fierce criticism from Vivus's largest shareholder.