April 1, 2026 — Three decades ago, in a lab at The Rockefeller University in New York City, Jeffrey Friedman, MD, PhD, observed a paradox that would forever change our understanding of obesity.
His subjects, a rare strain of mice, ate voraciously yet lacked energy. They were infertile, had compromised immune systems, and couldn’t regulate body temperature. They looked obese but behaved as if they were wasting away.
“Pretty much every organ system was altered,” recalled Friedman, a professor of molecular genetics.
In a landmark 1994 paper, he reported that the mice were missing a hormone called leptin that tells the brain to feel full. Drugmakers pounced, and headlines heralded the coming of a miracle weight loss drug. But clinical trials fell short, and interest faded.
“Clinically, with very few exceptions, leptin has been a total bust,” said Philipp Scherer, PhD, a professor at UT Southwestern Medical Center in Dallas who’s been studying fat cells for more than 30 years.
That story is being rewritten — and it’s a comeback tale.
With researchers and Big Pharma now racing to improve blockbuster GLP-1 weight loss drugs, leptin has resurfaced as a promising candidate. Estimates show half of patients quit the drugs within a year — often due to side effects — and some believe leptin could be the secret ingredient to quell adverse reactions while delivering enhanced results. Beyond weight loss, synthetic leptin is providing relief to people with rare metabolic diseases, while clinicians prescribe it off-label for eating disorders, and scientists, like Scherer, explore whether lowering the hormone could improve health.
“We haven’t even scratched the surface for leptin’s potential,” said Elif Oral, MD, an endocrinology professor at the University of Michigan in Ann Arbor.
How Leptin Works
Friedman describes leptin as a chemical messenger, keeping weight stable by telling the brain how much fat the body has on board.
When fat cells abound, leptin surges, signaling the brain that the body is satisfied. When fat runs low, leptin recedes and appetite increases. A big drop in leptin triggers a starvation response, compelling the brain and body to save energy.
When Friedman discovered the hormone — which he named after the Greek word leptos, for thin — the drugmaker Amgen licensed it for $20 million. Company execs imagined a simple fix: Give people with obesity a leptin-like drug called metreleptin (Myalept), and they would eat less and lose weight. But that approach only worked in a small subset of people who, like those mice, had genetically low leptin.
As it turns out, most people have too much leptin — so much that their leptin receptors have numbed. The condition, known as leptin resistance, is difficult to define and not routinely tested for, but doctors say it can lead to insatiable hunger, sluggish metabolism, and stubborn weight gain, among other health problems.
Friedman compares it to type 2 diabetes. In type 1 diabetes, people lack insulin. In type 2, which is far more common, they have too much — desensitizing their system to its effects.
Research suggests that fewer than 10% of people with obesity lack leptin. The other 90% are leptin resistant.
The question facing scientists and drug developers now: Is it better to raise leptin, lower it, or orchestrate a happy medium? That may depend on the patient.
Starving for Leptin
Oral, the Michigan endocrinologist, vividly remembers the day a desperate father walked into her clinic cradling his 14-year-old daughter. The girl was rail thin, weak, and covered with painful lesions. Her triglycerides were off the charts, and her liver was huge.
Oral wondered why someone with so little fat would have some of the worst obesity-related complications she’d seen. She learned the culprit was lipodystrophy, a rare disorder in which the body lacks the fat cells needed to make leptin.
“We tend to look at fat as something we do not want,” Oral said. “In reality, it is this beautiful tissue that stores energy and sends all kinds of important signals.” Without the leptin signal, the brain panics, pausing tasks like reproduction and fighting infection to focus on one mission: finding food.
Without healthy tissue to store lipids, the body crams them into inopportune places, leading to fatty liver disease and fat-filled skin lesions called xanthomas. Congenital lipodystrophy affects an estimated 1 in 10 million, but the 30 or so other lipodystrophies may collectively affect as many as 1 in 10,000, Oral said. Until recently, there was no treatment.
Oral changed that when, in July of 2000, she started giving that teenage patient daily leptin injections.
“All of her labs normalized before my eyes,” Oral said. “It was one of the most gratifying moments of my life.”
In 2014, Oral helped convince the FDA to approve metreleptin for the most serious forms of lipodystrophy. But her work is not done. She has since conducted clinical trials of leptin therapy for metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease), with modest results.
She also points to new research from Switzerland suggesting that leptin may alleviate depression and restlessness in women with severe anorexia and make them feel good about eating again.
“You would think the last thing you’d want to do is give their brain a signal associated with not wanting to eat,” Oral said, “but leptin can also be a happy signal that says, ‘I have enough energy onboard now and can think of other things.’”
Leptin Cocktails for Weight Loss
For years after the highly publicized failure of leptin for treating obesity, drug companies searched for the next weight loss miracle.
“Nobody made any money,” said Randy Seeley, PhD, director of the Michigan Nutrition Obesity Research Center at the University of Michigan and a paid consultant for several pharmaceutical companies, including Novo Nordisk (Ozempic, Wegovy) and Eli Lilly (Mounjaro, Zepbound). For a time, this dulled Big Pharma’s appetite to fund leptin research. But the calculus changed with the arrival and extraordinary success of GLP-1 receptor agonists. “It’s a whole different ball game,” Seeley said.
GLP-1 agonists mimic a gut hormone that modulates appetite, via a pathway that likely evolved to protect humans from foodborne toxins — explaining the chronic nausea and other gastrointestinal distress.
Animal studies show that leptin, which works through a different brain mechanism, can be given in high doses with little nausea. Another plus: It has been shown to prompt the body to burn fat while preserving lean tissue — leading some to theorize that drug combinations targeting the leptin pathway could help minimize the muscle loss so often associated with GLP-1s.
GLP-1s manage short-term appetite control, while leptin acts on longer-term mechanisms to keep weight stable. When people lose weight on GLP-1 agonists, their leptin tends to fall — which can increase hunger, decrease energy expenditure, and sabotage weight maintenance long term.
“If I now add back leptin, can I normalize your biology, getting you better weight loss?” Seeley asked.
His lab and others intend to find out.
In one recent study, done in conjunction with Novo Nordisk and published in Science Translational Medicine, Seeley’s team developed a molecule that activates both leptin and GLP-1 receptors in neurons. They found that dual activation led to greater weight loss in mice than targeting either receptor alone.
The combo worked best in obese mice that lacked leptin (rather than those with diet-induced obesity) — a finding that demonstrates the importance of the leptin-targeting component. Seeley acknowledged there are GLP-1s out there that work better than the combination they tested, but the proof-of-concept study is an important step forward in showing the potential synergy of combinations. He imagines a day when drug companies could use less GLP-1-activating compounds while targeting other receptors — achieving weight loss with fewer side effects.
The work could transform how researchers imagine and create new obesity treatments, opening the door “to co-targeting of short- and long-term regulatory pathways,” said Catherine Charneski, PhD, senior editor of the journal, in an accompanying summary.
About a half-dozen other labs have also come up with combo drugs aimed at targeting three or four metabolic pathways, including leptin’s.
“While it may not work on its own, leptin has returned to be part of the alphabet soup we are using to try to develop better and better therapies for obesity,” Seeley said.
Battling Leptin Resistance
Other labs, including Friedman’s, are taking on leptin resistance.
In one study, published in 2025, Friedman and his colleagues at Rockefeller University discovered cellular mechanisms responsible for keeping the brain’s energy center, the hypothalamus, from recognizing the leptin signal.
Even more promising, they found that a commonly used drug, known as rapamycin, could restore leptin sensitivity in mice.
“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,” said Kristina Hedbacker, PhD, a co-author on the recent paper and member of Friedman’s lab. “It’s really exciting to think that there may be means for addressing this.”
Scherer is taking a different approach. He argues that lowering leptin could be the key to battling obesity, diabetes, and many other age-related health problems.
“We all agree that if you don’t have leptin at all, there are huge issues. But leptin also has a dark side,” said Scherer, who has developed a monoclonal antibody that scavenges and neutralizes the hormone in mice.
Excess leptin can promote leptin resistance, worsen diabetes and obesity, and increase the risk for other diseases, including fibrosis and cancer, he said. Yet due to our modern diets, almost all of us have too much leptin, particularly as we age.
Someday leptin-reduction therapies could be used to restore sensitivity to the hormone, Scherer said.
“Our proposal may sound revolutionary, but in a way it is not at all,” he said. “It’s just taking what we know from 30 years of research and turning it upside down. Instead of thinking about how we can add more leptin to the system, let’s think about how we can have less and achieve the same thing.”
How to Support Healthy Leptin Levels
While scientists work on new medications, some research suggests you can improve your leptin response naturally:
Prioritize sleep. Studies show that lack of sleep can trigger leptin to drop, increasing hunger and cravings.
Avoid highly processed foods. Processed foods can drive inflammation and boost leptin, potentially worsening resistance. In one study, teenagers who ate more processed foods had significantly higher leptin levels.
Exercise regularly. High-intensity exercise may help reduce leptin levels while increasing leptin signaling in the brain, counteracting resistance.
Eat plenty of protein and limit sugar and fat. Some small studies suggest that high-fat, high-sugar diets that are low in protein may drive leptin resistance.
Avoid crash diets. These can backfire by causing too much weight loss too fast, prompting leptin to plummet and appetite to spike.
