Researchers discover a cause of leptin resistance—and how to reverse it

Worldwide obesity rates have more than doubled since 1990, with nearly a billion people now falling into the category. Though a complex interplay of genes, diet, and environment contribute, 90% of cases share one thing in common: leptin resistance.

In lean individuals, fat cells produce the hormone leptin, which suppresses appetite. But in most individuals with obesity, this signal fails to register. Why this happens has been a mystery for more than three decades, ever since Jeffrey M. Friedman’s laboratory at the Rockefeller University cloned the leptin gene in 1994.

But now Bowen Tan, Kristina Hedbacker, and other researchers in Friedman’s Laboratory of Molecular Genetics have discovered a neural mechanism involved in leptin resistance—and, crucially, a way to reverse it in mice using a well-known drug. As the researchers describe in a new paper in Cell Metabolism, the drug rapamycin restores leptin sensitivity to diet-induced obese mice, leading to significant loss of fat with only minimal effects on muscle.

“Before our research, the cause of obesity in diet-induced obese mice was unknown, leaving a critical gap in our understanding of how leptin resistance develops and how it can be reversed,” says Tan, co-first author and a graduate student in Friedman’s lab.

“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 co-first author Hedbacker, a research specialist at HHMI and a member of Friedman’s lab. “It’s really exciting to think that there may be means for addressing this.” 

Too much of a good thing

Long before plant agriculture and animal domestication provided more reliable access to nutrients, humans routinely faced starvation. That’s when the leptin circuit evolved. Neurons in the hypothalamus—the brain’s energy-balance regulator—pick up satiety signals from fat, which secretes leptin; a high amount of the hormone signals that there are adequate fat stores and the energy tank is full, while a low leptin level indicates that the body is running on fumes.

Our brains retain this system for regulating food consumption, even as conditions around it have drastically changed, with more people having access to high-calorie foods than ever before. Data suggest that as weight is gained and leptin levels continually rise, the brain gradually stops responding to leptin.

“This phenomenon is analogous to insulin resistance, which is the most common cause of diabetes and a condition that develops over time, due, in part, to chronically elevated insulin levels,” Hedbacker says. “Similarly, most people with obesity have high leptin, but reception of their leptin signaling is blocked. This makes it very difficult to lose weight, because the brain does not receive the appropriate signal of how much fat is stored.”

With this in mind, Tan and Hedbacker set out to identify biomarkers in the 10% of patients with obesity who are leptin sensitive and could potentially benefit from leptin treatment. They looked in both leptin-sensitive and leptin-resistant mice.

What they discovered sent them down an unexpected path. They found that in leptin-resistant mice, the levels of two essential amino acids are dysregulated in response to leptin. These two amino acids, methionine and leucine, are known activators of a signaling molecule called mTOR (short for “mammalian target of rapamycin”). Leptin-sensitive animals showed no such dysregulation.

“With this as a starting point, we found that mTOR is hyperactive in specific brain regions and cell types in obese animals,” Tan says.

Weight loss

To investigate further, the researchers tested the effects of rapamycin, an mTOR inhibitor, in four groups of mice: leptin-sensitive mice fed a low-calorie chow diet, mimicking people who remain lean; mice fed a high-fat diet that developed leptin resistance, similar to people who develop obesity; and two sets of obese mice that were leptin deficient but responsive to the hormone. These mice were fed either the low-calorie chow diet or the high-fat diet. 

The results were striking: “Obese mice fed a high-fat diet and treated with the mTOR inhibitor rapamycin lost significant amounts of weight, which—similar to leptin treatment in leptin-sensitive animals—was primarily due to a decrease in the amount of adipose tissue,” Tan says.

Loss of fat mass without muscle mass is characteristic of leptin treatment, but it’s unusual for weight loss in general. For example, weight loss achieved by dieting or treatment with highly effective anti-obesity medications such as Ozempic leads to a significant loss of both fat and muscle.

They then investigated which cell types in the brain were the target of rapamycin, focusing on a dozen cell types in the hypothalamus, where leptin is known to act. Using single-cell sequencing, Tan found that rapamycin treatment exerted significant effects on neurons in the hypothalamus that express a gene known as POMC. These neurons are known to mediate leptin’s weight-reducing effects.

“We found that rapamycin reduced mTOR in POMC neurons and restored their receptivity, essentially resensitizing the animals to leptin and leading to a decreased size of fat depots relative to muscle mass,” Hedbacker says. 

Defects in POMC-expressing neurons are also known to cause leptin resistance and obesity, Friedman notes, adding, “it was satisfying to find that an acquired form of leptin resistance targets this same pathway.”

By showing that is possible to restore leptin signaling, the findings could potentially lead to new obesity treatments. Future research in Friedman’s lab will explore why a high-fat diet elevates mTOR signaling in the brain. The lab will also try to develop means for inhibiting mTOR specifically in POMC neurons to avoid potential side effects of systemic rapamycin use, which is linked to glucose intolerance and potentially diabetes.