Ask Jeffrey Friedman what causes obesity, and he can answer you in one word: leptin.
“In my view, obesity is, to a large extent, driven by the dynamics of the leptin system,” says Friedman, the geneticist at Rockefeller University who discovered the hormone more than 30 years ago.
Since then, obesity research has exploded. Scientists have published more than 44,000 papers exploring how leptin, a hormone secreted by fat cells, interacts with the brain to quell appetite — and what happens when this complex pathway malfunctions.
Friedman’s discovery helped to radically shift our understanding of obesity, from a failure of willpower to a problem with the brain.
“We now realize that if weight loss feels harder than it should, there is a biological explanation,” says Shagun Bindlish, MD, an obesity medicine specialist with One Medical in California. “Hormones like leptin play a powerful role.”
Research suggests that about 10% of people with obesity don’t make enough leptin. The other 90% are “leptin resistant,” meaning they have plenty, or even too much, leptin — but their brain has grown desensitized to its satiating effects.
What can people who are leptin resistant do about it?
Despite decades of research, that answer remains elusive.
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What Is Leptin?
Friedman was studying animal behavior when he came upon a unique strain of overweight mice that had a voracious appetite and didn’t move much.
In a landmark paper published in Nature in 1994, he reported the mice had a defect in a single gene — a gene responsible for producing a hormone critical for making them feel full. He named the hormone leptin, for the Greek word leptos, meaning thin.
Today, we know that leptin serves as a chemical messenger, keeping weight stable by telling the brain how much fat the body is carrying at any given time.
Here’s how a healthy system works: When fat cells are abundant, leptin surges, signaling there’s plenty of fuel on board and nudging us to eat less. When fat cells dwindle, leptin recedes and appetite grows. When leptin falls really low, it tells the brain to conserve energy.
“The brain essentially thinks [you] are starving,” so you eat more and move less, said Friedman.
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The Leptin Fix That Didn’t Work
Early on, scientists imagined a simple fix: Just give people with obesity more leptin — or a leptin-like drug — and they would be less hungry and lose weight.
But despite high hopes, that approach only worked in a small subset of people.
Why?
As it turns out, most people with obesity have chronically high, not low, leptin levels; their brains just misread it.
Friedman draws comparisons to diabetes. In type 1 diabetes, which is relatively rare, people lack insulin. In type 2 diabetes, which is far more common, they make too much insulin — so much that their cells become desensitized to it.
In people who are leptin resistant, “even if they have enough fat stores, the brain is just not getting the signal,” Bindlish says. “This leads to ongoing hunger, reduced satiety, reduced metabolism, and difficulty keeping weight off even after they lose it.”
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Can Leptin Resistance Be Reversed?
Doctors typically don’t test for leptin resistance. But Google searches for the term are up, according to the Obesity Medicine Association. And Bindlish says her patients often ask what they can do to overcome it.
She recommends lifestyle changes, but with a caveat.
“Healthy habits can improve how the body responds to leptin, but they cannot completely reverse the resistance once it is established,” she says.
She advises her patients to do the following:
- Prioritize sleep. Studies show that sleep deprivation can impact leptin regulation in ways that increase hunger and exacerbate cravings.
- Avoid highly processed foods, which can drive inflammation, interfering with signaling in the brain’s appetite centers. Such foods may also boost leptin to unhealthy levels, which, when done chronically, can exacerbate resistance. One study of 400 teenagers found that those who ate more processed foods high in saturated fat and simple sugars and low in protein had significantly higher leptin levels.
- Exercise regularly. Some evidence suggests that exercise, particularly high-intensity exercise, can help counteract leptin resistance by reducing circulating leptin levels and increasing leptin signaling in the brain.
- Eat more protein and less fat and sugar. Some small studies have suggested that diets low in protein and high in fat, carbohydrates, and fructose and sucrose (sugars) drive leptin resistance.
- Avoid yo-yo diets. Losing too much weight too fast can prompt leptin levels to plummet, pushing the brain into a “starvation mode” that boosts appetite and kills energy.
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New Medications on the Horizon
No concrete evidence exists to confirm that lifestyle changes can reverse leptin resistance, but Friedman believes that medications someday could.
In one study, published in March 2025, he and his colleagues identified cellular mechanisms that prevent the leptin signal from reaching the brain’s energy center, the hypothalamus. Even more promising, they found that a commonly used drug, known as rapamycin, could restore leptin sensitivity in mice.
More research is necessary, but Friedman and his colleagues imagine a day when medications targeting the leptin pathway (longer-term appetite signaling) could be given alongside existing obesity medications (which work on shorter-term signaling) to help people maintain weight loss long term — minus the muscle loss that often occurs with weight loss drugs.
“Even though Jeff Friedman discovered this powerful hormone back in 1994, its full potential to help people lose weight hasn’t been realized because most obese patients have acquired resistance to leptin,” says Kristina Hedbacker, PhD, a co-author on the recent paper and a researcher in Friedman’s lab. “It’s really exciting to think that there may be means for addressing this.”
