They rose to fame as the world’s fattest mice. At about 130 grammes, the rodents were “the equivalent of 600 pounds in humans,” says diabetes researcher Philipp Scherer. They were born to genetically engineered mouse parents in his lab at the University of Texas Southwestern Medical Center.

One set of parents lacked the hormone leptin, an appetite suppressant that signals when it’s time to stop eating. The other parents overproduced the hormone adiponectin, churned out by fat cells, which is thought to support metabolic health, protecting against obesity-linked diseases such as type two diabetes.

Scherer’s mouse pups melded their parents’ traits. They ate constantly and became obese. But unlike other leptin-deficient mice (and people), the animals had healthy cholesterol and blood glucose levels and didn’t develop metabolic illnesses such as type two diabetes.

“They were exceptionally quote-unquote healthy,” Scherer says, though he wonders whether it’s possible to be truly well while carrying such a considerable fat burden. Despite their metabolic health, the mice didn’t live a normal life span: Their weight left them so off balance that they often flipped over and got stuck, causing dehydration and death.

Still, to Scherer, who described the animals in 2007 and continues to study them, the rodents sharpened an emerging message for people as well as mice: Weight and health can be uncoupled. Many researchers and doctors – and broader societies – take it as a given that obesity means ill health. In fact, says Ruth Loos, who studies the genetics of obesity at the University of Copenhagen, “We can be obese but remain healthy.”

Scherer, Loos, and other researchers worldwide are examining genes, animal models, and humans to understand how factors such as the distribution of fat in the body and the nature of fat itself can blunt or compound any health impacts of extra weight. The researchers are also working to define metabolically healthy obesity (MHO) and examine how common it is and how long it persists.

Beyond the research lies a knotty practical question: what the science means for people with obesity and the doctors they see. Undoubtedly, “There are subtypes of obesity,” with some more harmful than others, says Sadaf Farooqi at the University of Cambridge. “You’ve got this massive variation that must be driven by other underlying factors.”

At the same time, Farooqi suggests, people who qualify as overweight or obese should generally try to lose weight. “There is a clear correlation between gaining weight and increased risk of type two diabetes,” she says, “even if you don’t get it right now.” Furthermore, she and others say, obesity is associated with health problems well beyond metabolic abnormalities, including various cancers and wear and tear on joints.

Others, particularly advocates concerned about discrimination against fat people, make a different argument: Hammering people with advice to “lose weight!” is misguided. “It’s very clear that there are a lot of people in that category called obese [who] don’t have any signs of disease and live long, healthy lives,” says Lindo Bacon, a physiologist, author, and advocate for body positivity affiliated with the University of California, Davis.

Bacon says a relentless focus on weight loss can come at the expense of vital medical care. For example, “My father and I both went to orthopaedic surgeons because we were having bad knee pain.” Bacon, whose weight qualified as normal, was offered surgery after physical therapy failed, but Bacon’s father was told only to lose weight.

 “My father went to his death with knee problems. … He could have benefited from stretching, strengthening, knee surgery,” Bacon asserts with frustration. “He didn’t get that.”

Though agreeing that obesity and ill health can travel together, Bacon insists fat itself is not a major player in disease. Social determinants of health, such as poverty, discrimination and access to healthy food, are likely far more important, Bacon argues.

And indeed, some studies have shown that people with obesity who don’t have metabolic dysfunction are often better educated and wealthier than those with obesity-associated health problems.

Many scientists say the evidence is clear that excess fat can pose significant health risks and that losing weight can improve health. But they agree with advocates that care for people with obesity needs to shift from simply pressuring them to shed weight, which often fails.

“I’ve worked with so many people who’ve gone through this cycle of losing and regaining and losing and regaining,” says Cynthia Bulik, a clinical psychologist and expert in eating disorders at the University of North Carolina, Chapel Hill, and the Karolinska Institute.

“It’s created mental torment, it affects their relationships, it affects their social life. It affects everything.” Scientists like Loos hope their work can move the focus away from body weight and toward measurable markers of metabolic health that can be more precisely and effectively targeted.

• A Nature magazine report