The "key discovery", which centres on the system that regulates physical activity levels, has been made by scientists in Scotland and China.
The study raises the prospect that personalised pills could be developed in future to help those who are less inclined to exercise, experts said.
Scientists from the Chinese Academy of Sciences, Institute of Genetics and Developmental Biology (IGDB) in Beijing and the University of Aberdeen compared normal mice with those that had a mutation in a gene called SLC35D3.
They discovered that SLC35D3 produces a protein which plays a key signalling role in the brain's dopamine system, the system which carries out a range of functions including regulation of physical activity levels.
Specifically, they found that the gene is important for transporting a type of dopamine receptor from where it is made inside a cell to the cell's surface, where it can then bind with the nerve-signalling chemical dopamine.
But mice with this gene mutated had far fewer of this type of dopamine receptor on the surfaces of their brain cells.
Instead, the dopamine receptors were stuck within the cell, meaning that their signalling process was not functioning properly, the scientists found.
But when the affected mice were treated with a drug that activates dopamine receptors, the problem was reversed and the mice became more active and lost weight.
Study leader Professor Wei Li, of the IGDB, said he was excited about the findings.
"We discovered that mice with this gene mutation were typical couch potatoes," he said.
"They walked only about a third as much as a normal mouse, and when they did move they walked more slowly. The mice became fat and they also developed other symptoms similar to a condition in people called metabolic syndrome - a medical term for those with a combination of risk factors related to diabetes, high blood pressure and obesity."
The researchers also screened 400 overweight Chinese patients with metabolic syndrome and found that two of them had mutations in the SLC35D3 gene.
The scientists suggest that in future people with metabolic syndrome may be screened to see if they have such a mutation. If so, drugs could perhaps be offered as a treatment.
Prof Li went on: "What was of particular interest, was that when we gave the mice a drug that acted on the dopamine signalling system, the genetic defect could be overcome and the mice became more active and thinner.
"A long-standing prescription in combating obesity is to mind your mouth and move your legs. However, genetics contributes to the reluctance to move in some obese people. Medical treatments will in the future be tailored to fit a person's individual genetic make-up."
Co-author of the research paper Professor John Speakman, who works between the University of Aberdeen and the IGDB, said: "Although only about one in 200 people may have these 'rare' mutations, there are a very large number of people worldwide that have metabolic syndrome.
"Consequently, the population of sufferers that may benefit from being treated with dopamine receptor drugs runs into many millions of patients."
The study is published in the journal PLOS Genetics.