They rose to fame as the world’s fattest mice. At about 130 grams, 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 2 diabetes, reports sciencemag.org.
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 2 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 2 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 orthopedic 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.
RISING OBESITY RATES have set off alarm bells for years. In 2018, 42% of U.S. adults were obese, up from about 30% 2 decades earlier, and prevalence is climbing rapidly in other countries, as well. The U.S. Centers for Disease Control and Prevention (CDC) defines obesity as having a body mass index (BMI) of at least 30, a calculation made by dividing weight in kilograms by the square of height in meters. (Although the value of BMI has been questioned, it remains a common metric in medicine and scientific studies.)
Scientists have long explored links between obesity and health problems. For example, according to a 2020 study in Obesity Science and Practice of almost 3 million U.K. adults tracked for an average of 11 years, people with a BMI between 30 and 35 had a risk of type 2 diabetes five times higher than that of people whose BMI was defined as normal. For a BMI of 40 to 45, the risk was 12 times higher. Obesity is also associated with a higher risk of heart disease, stroke, sleep apnea, certain cancers, and osteoarthritis.
Yet many people with obesity have healthy cholesterol and blood glucose levels, whereas many lean people do not. “You go to an obesity clinic, [where] people weigh 120 kilograms, 140 kilograms. Some have problems and some don’t,” says Antonio Vidal-Puig, who studies and treats metabolic disease at Cambridge. Conversely, he notes, patients who weigh 70 or 80 kilograms might be insulin resistant and have diabetes. Trends also vary by ethnicity. People of South Asian ancestry “develop diabetes without the levels of obesity in other populations,” Farooqi says. “We’re not all the same.”
Scherer’s mice offered a clue to the variation: Their fat was stored under the skin rather than in muscle or in organs such as the liver. That pattern aligned with what obesity researchers and doctors have observed in people. Large population studies have shown that people with excessive visceral fat, deep in the abdomen, are at higher risk of health problems than people with high volumes of subcutaneous fat, under the skin of the thighs, arms, and backside. When someone has high visceral fat, “that’s when metabolic disease occurs,” says Bernard Zinman, an endocrinologist at the University of Toronto. Visceral fat generates inflammatory molecules, and imaging studies have shown it’s associated with fat buildup in the liver, pancreas, and muscle.
By contrast, subcutaneous fat can nurture good health, serving as a store of energy and helping cushion muscle and bones. Some evidence indicates people with ailments such as heart failure or cancer fare better if they are modestly overweight than if they are lean. In 2005, a CDC and National Cancer Institute research team reported that overall, people who were overweight but not obese had slightly lower mortality rates than people whose weight qualified as normal. “Fat is our friend, and we need it,” Scherer says. “If you don’t have adipose tissue, you really are in big trouble.”
Subcutaneous fat is also a safety valve: Without such a zone for stashing extra fat deposits, they travel to the visceral region. Rare disorders called lipodystrophy syndromes illustrate this vividly. Affected people cannot accumulate subcutaneous fat and appear thin, yet they develop diabetes and fatty liver disease.
“Do you have all these walk-in closets” for healthy fat storage, Zinman asks, “or do you live in a condo where you have just one cupboard? Some people have tremendous ability to store calories, and others don’t.”
Another clue about the value of fat storage capacity—and subcutaneous fat itself—comes from a class of diabetes drugs called thiazolidinediones introduced in the late 1990s. Intriguingly, while reducing blood glucose levels they also caused patients to gain weight. Several studies reported that the drugs help convert fat precursor cells into mature fat cells in subcutaneous regions. Patients added fat subcutaneously, which appeared to reduce inflammation and improve the body’s response to insulin.
“It’s not how fat you are, it’s what you do with it that counts,” Vidal-Puig titled a commentary he co-wrote in 2008. At the same time, Vidal-Puig expresses a quandary he and colleagues face: He is reluctant to use the term MHO, which he worries could mislead people into thinking, “it’s OK to be obese.”
“We are not saying that,” he says. Rather, some people “are healthy because they are resilient to obesity.” Vidal-Puig wants to stick to the science of that resilience by exploring how obesity can coexist with measures of health. “We are explaining how it works.”
LOOS HAS HUNTED for an explanation for 10 years, ever since a strip of DNA sent her down an unexpected path. She was part of a research group searching for genes that predispose people to extra body fat, and three stretches of DNA popped up. One appeared to boost body fat in the hips and thighs—and yet it sat next to a gene called IRS1, which was known to reduce risk of cardiovascular disease and diabetes. The discovery, the first of its kind, “set us off,” Loos says, and she began to try to tease apart fat and metabolic health.
In February, she and colleagues reported more gene variants that appear to have similar double action. Writing in Nature Metabolism, they cataloged 62 variants associated both with more fat—including higher BMI and higher body fat percentage—and a lower risk of cardiac and metabolic diseases. The DNA included areas that control inflammation, energy expenditure, and insulin signaling.
Loos used to work one floor below Vidal-Puig at Cambridge, and the two are now collaborating: He is studying some of the DNA variants she identified. Vidal-Puig is especially interested in genes that may lead to changes in fat tissue over time, such as helping improve storage capacity for subcutaneous fat or reducing inflammation. He’s also exploring the role of genes in fibrosis, a thickening or scarring of connective tissue that promotes harmful inflammation and may contribute to conditions including fatty liver disease. “We know that obese people have more fibrosis in their adipose tissue,” he says.
Meanwhile, Scherer—creator of the world’s fattest mouse—continues to probe the role of adiponectin. He notes that unhealthy fat, with lots of inflammation and fibrosis, generates less adiponectin. In the mice, in contrast, a surfeit of the hormone appears to expand their subcutaneous storage capacity. Adiponectin also seems to protect the mice from becoming metabolically unhealthy as they age, Scherer and colleagues reported in eLife this year.
On the human front, Samuel Klein, director of the Nutrition Obesity Research Center at Washington University in St. Louis, runs one of the most exhaustive studies yet. Since 2016, he and colleagues have administered a battery of tests to three groups, for which he’s still recruiting: 45 metabolically healthy obese people, 45 metabolically unhealthy obese people, and 25 lean people. The researchers collect at least one muscle and fat biopsy, take blood samples, infuse insulin to measure how it regulates glucose metabolism in muscle, and more. Participants are randomized to different diets, including a Mediterranean diet and a plant-based diet, to test how each affects metabolism.
Klein says he wants to understand why some people with obesity are “resistant” to its downsides. He’s especially keen to determine whether subcutaneous fat is different in metabolically healthy and unhealthy groups with obesity. In a paper this year, his group reported greater production of fibrous tissue in the fat of a metabolically unhealthy group than in counterparts who are metabolically healthy. Of the questions to be tackled, he says, “It’s endless.”
Still, the science bolsters what plus-size athletes, including weightlifters, dancers, and marathon runners, have long declared: Being fat doesn’t have to mean being unhealthy. “There are people,” as Loos’s data show, “who are genetically predisposed to obesity [and] have low cardiac risk, and that’s pretty interesting,” Bulik says. “They might be able to survive in a larger body” without metabolic ill effects.
But just who is so fortunate isn’t clear. No agreed-on definition of MHO exists, Klein says; anywhere from about 6% to 60% of people qualify. Women, younger people, and those with BMIs under 35 are more likely to meet MHO criteria. Many studies define MHO as having two or fewer features of metabolic syndrome, a constellation of risk factors that boosts the likelihood of cardiovascular disease and diabetes and includes a large waistline, high blood pressure, low HDL (“good”) cholesterol, high triglycerides, and high blood sugar. By another definition—having at most one of six metabolic concerns—roughly 75% of people whose weight qualifies as normal and 32% of people with obesity are metabolically healthy, Klein says.
“Making these decisions isn’t easy,” agrees Matthias Schulze, an epidemiologist who studies risk factors for heart disease and diabetes at the German Institute of Human Nutrition. This year, Schulze and his colleagues proposed a new definition for MHO based on data from two existing cohorts with a range of BMIs, one including about 12,000 U.S. adults and the other, 374,000 U.K. adults. The researchers hit on three key criteria: systolic blood pressure below 130 without medication, no diabetes, and a waist-to-hip ratio of less than 0.95 for women and less than 1.03 for men.
About 40% of the U.S. cohort and 20% of the U.K. cohort met that definition, and over 14 years, those people appeared no more likely to die of heart disease, stroke, diabetes, or other causes than metabolically healthy people of normal weight. (The finding only applied to people with a BMI under 40; above that, risk of death was elevated regardless of metabolic health.) But Schulze’s work pointed to a wrinkle of MHO: In the U.S. group, in which a higher proportion qualified as metabolically healthy, the average age was 41; in the U.K. group it was 56.
The age gap may not be the only explanation for the difference, but it’s a “plausible” contributor, Schulze says—and one supported by other studies. “Most people who are metabolically healthy [and] obese at one point transition to being metabolically unhealthy,” says Frank Hu, co-director in the program of obesity epidemiology and prevention at the Harvard T.H. Chan School of Public Health. In 2018, Hu, Schulze, and colleagues co-wrote a paper in The Lancet Diabetes & Endocrinology in which they examined outcomes for more than 90,000 women in the Nurses’ Health Study, a decadeslong project that gathers health and other data. The pair and their colleagues found that over 20 years, 84% of women with MHO (defined as having healthy cholesterol and blood pressure levels and no diabetes) became metabolically unhealthy—which, Hu argues, suggests MHO is transient and “not benign.” But he also notes that more than two-thirds of the normal-weight women developed some sort of metabolic issue in that time, too.
Amid that complexity, some are calling for a more nuanced approach to caring for people with obesity, putting greater emphasis on multiple measures of health. “We tend to get hung up on obesity and weight in part because they’re visible,” says David Allison, a prominent obesity researcher and dean of the Indiana University, Bloomington, School of Public Health. “If we walk into a room and shake hands, you see my weight. You don’t see my cholesterol level, you don’t see how much fat is in my liver.”
Clinicians and researchers like Bulik and Vidal-Puig favor focusing less on a person’s BMI and more on cardiac and metabolic markers such as triglycerides and blood pressure. Schulze adds that waist-to-hip ratio, a component of his risk calculator, is something a doctor can measure. One way to strive for a more metabolically healthy body is with movement or exercise, which can improve response to insulin and help clear fat from the liver, even without weight loss, Vidal-Puig says. “It’s not about fat, it’s about being fit. [That’s] what I tell people.”
In Klein’s view, obesity treatments should aim for metabolic improvement as well as weight loss. “If you lose 3% of your body weight” and improve metabolic outcomes, “is that worse than losing 8%” and seeing no such improvement? he asks. “Eight percent would be rewarded, whereas 3% would be, ‘You’re not sticking with the program.’” Klein hastens to add that weight loss may pay off in other ways, by reducing the risk of various health problems. And perhaps partly because of social pressures, many individuals simply prefer to be leaner.
When someone who is fat walks into a doctor’s office for a checkup, Bacon says, “the first thing you should think about … is ‘What kind of advice would I give a thinner person?’” The guidance won’t necessarily be identical—for example, they note, a fat person may encounter stigma a thin person wouldn’t when exercising at a gym. “But I think that, to get away from weight bias, one of the first things people can do is try to take weight out of the picture,” Bacon says, “before they come to consider it.”
— Article by Jennifer Couzin-Frankel Jennifer. She is a longtime staff writer with Science, covering stories in biomedical and clinical research and bioethics.