Obesity shaped Anna Olson's earliest notions of herself, when she saw a photo and thought, "Oh, I look different than the other kids."
Olson's obesity began in toddlerhood, ran in her family, and left her with a chronic hunger hard to satiate. Dozens of diet, drug and exercise regimens didn't work, and advice from doctors was always the same: Eat less. "And I'm kind of like, 'Well, it's what I'm doing now. What else can I do?'" she says, and the response, again, was: "Well, you just got to eat less."
In fact, science now shows obesity is far more complex — with numerous genetic, biological, neurological, lifestyle, metabolic and behavioral factors contributing to it.
Root causes vary
Doctors, patients and drug companies have learned a lot more in recent years about obesity and what works — or doesn't — since the new class of obesity treatments known as GLP-1 drugs have come to market. Although obesity manifests one way — excess weight — doctors say there are perhaps dozens of different forms of it. For treatment to work, therefore, root causes must be identified, then addressed, for each person. Obesity doctors and researchers say within several years, they expect treatment will be more customized to meet the needs of each patient.
For Olson, genetic testing indicated she likely has several genetic and hormonal factors setting her hunger and satiety sensors out of whack. One of the GLP-1 drugs — Ozempic — worked briefly, but it turned out another, Zepbound, better recalibrated Olson's hormone imbalance. It was only when she started tackling her specific obesity drivers that Olson began losing lots of weight — 65 pounds to date, as she remains on the medicine. "I've been able to keep it off," she says.
Popular drugs a precursor to precision medicine?
Use of GLP-1 drugs is already huge and is set to become even more common, as the medicines become cheaper, with more variations, including the recently launched, easier-to-use Wegovy pill from Novo Nordisk.
Ozempic and Wegovy are the brand names for a drug called semaglutide. Zepbound and Mounjaro are the brands of a drug called tirzepatide. Both are GLP-1 agonists, and tirzepatide blocks an additional hormone, known as GIP.
Within a few years, doctors say, there also will be more ways to determine an individual's specific obesity factors, which will enable a more precise targeting of the root causes of their obesity, similar to how chemotherapies can target specific cancer subtypes.
The complex makeup of obesity might also explain why GLP-1s don't work for many people. A sizable minority experience side effects like nausea; studies have shown a significant portion of patients lose less than 5% of their body weight on the drug, though they may experience other metabolic improvements.
Obesity subtypes
"There are many types of obesity, and each type of obesity has a unique genetic predisposition," says Andres Acosta, a gastroenterologist and hepatologist at the Mayo Clinic. Acosta says early research indicates genetic markers might be measured to predict, for example, whether a person might not respond well to GLP-1 medicines.
Acosta is also co-founder of Phenomix Sciences, a company selling genetic testing through some doctors' offices; the testing is not covered by insurance.
The cheek-swab genetic test groups people into four basic obesity phenotypes (meaning observable traits): Hungry Gut, Hungry Brain, Emotional Hunger, and Slow Burn. (A person might belong to more than one of these groups.) Each category has different hormonal or lifestyle factors that drive obesity. For example, someone with emotionally driven eating habits might not benefit as much from GLP-1 drugs.
Acosta says also, those with abnormalities in their gut hormones tend to lose more weight on GLP-1 medicines, while some people with "Hungry Brain" genetic markers may have a broken neural pathway that prevents the drug from being as effective for that group. For those people, Acosta says, often earlier generations of weight-loss medicines — or a combination of new and old drugs — work best.
A workable treatment plan
Anna Olson says this kind of personalization was key. Through genetic testing, she found out her phenotype is "Hungry Brain." She also found out she has Bardet-Biedl syndrome, a genetic disorder that predisposes her to eat too much. Knowing that, she says, reduced her sense of stigma and helped her find the most fitting combination of medications for her.
Now 36, she says her cholesterol and blood sugar levels have improved, and she's closer to her dream of traveling further afield from her native Minneapolis. "When I was more overweight than now, there was absolutely no way that I could do that."
More precise diagnosis of specific forms of obesity is still a few years off, says Dr. Lydia Alexander, past president of the Obesity Medicine Association. But researchers are getting closer to understanding the variables that make a difference.
The chemistry of a person's gut microbiome, their proclivity toward addiction, or the molecular shape of their hormone receptors can all affect the drug's efficacy, she says. "The medication might be degraded faster in one individual than in another," she says, which might also explain the different responses to GLP-1s.
Alexander says that in all instances, adaptations in lifestyle are critical for a full and lasting response. In fact, a recent review of 37 studies on weight loss showed that those who rely on GLP-1 drugs tend to gain back the weight at a faster rate when they stop treatment, as compared to those who rely on behavioral change.
A 50-50 chance of success
Meanwhile, one of the downsides of popularized GLP-1 drugs is that they have raised people's expectations for rapid weight loss, says Dr. Jennifer Manne-Goehler, a Harvard metabolic disease specialist. She says roughly half of those who take GLP-1 drugs lose 15% or more of their weight, and "because the potential of those drugs is so incredible for that half, everyone who takes them thinks they're going to be in the half that have that experience."
Manne-Goehler says what's often forgotten is that obesity is a chronic, lifelong condition. "One tool does not work for each person, and one tool often is not enough over the lifetime of a person to control or to mitigate the health impact of that condition," she says. But over the next few years, she says, at least there will be more tools to better target treatment.
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