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 have leptin resistance in common.
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 Friedman, MD, PhD, together with Bowen Tan, Kristina Hedbacker, PhD, and other researchers in Friedman’s Laboratory of Molecular Genetics have discovered a neural mechanism involved in leptin resistance, and identified a way to reverse it in mice using the mTOR inhibitor rapamycin. The team found that rapamycin restores leptin sensitivity to diet-induced obese (DIO) 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,” said Tan, 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,” added Hedbacker, a research specialist at Howard Hughes Medical Institute and a member of Friedman’s lab. “It’s really exciting to think that there may be means for addressing this.”
Senior author Friedman, together with co-first authors Tan, Hedbacker, and colleagues reported on their work in Cell Metabolism, in a paper titled, “A cellular and molecular basis of leptin resistance,” in which they suggest their findings establish “.. a key pathogenic mechanism leading to obesity.”
“Obesity is the cardinal feature of metabolic syndrome and a worldwide public health problem,” the authors wrote. 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. “In lean animals, adipose tissue mass is tightly controlled by the hormone leptin (LEP), which functions as the afferent signal in a negative feedback loop that maintains energy balance,” the authors explained. “LEP reduces appetite, in part by activating α-MSH (POMC)-expressing neurons in the arcuate nucleus (ARC) of the hypothalamus.”
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 said. “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 at both leptin-sensitive and leptin-resistant mice. “Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown,” the authors noted.
What they discovered sent them down an unexpected path. The scientists 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 (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 said. For their study the researchers tested the effects of the mTOR inhibitor rapamycin 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. “Our finding that LEP sensitivity was inversely associated with plasma levels of mTOR activators led us to hypothesize that mTOR activation might diminish LEP sensitivity in DIO mice. We evaluated this possibility by treating DIO mice with rapamycin (RAP), a specific mTOR inhibitor,” they explained.
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 said. The authors further noted, “We found that RAP, a specific mTOR inhibitor, reduces body weight in DIO mice but not in mice with defects in LEP signaling or low circulating levels of the hormone.”
The team 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 then employed snRNA-seq to show that RAP treatment of DIO, but not lean mice, specifically induced gene expression in POMC neurons that promote LEP signaling and melanocortin production,” they wrote. “Further studies showed that POMC neurons and melanocortin signaling are necessary for RAP’s weight-reducing effects and that increased mTOR activity in POMC neurons is sufficient to cause LEP resistance.”
Added Hedbacker, “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.” Defects in POMC-expressing neurons are also known to cause leptin resistance and obesity, Friedman noted, adding, “it was satisfying to find that an acquired form of leptin resistance targets this same pathway.”
By showing that it is possible to restore leptin signaling, the findings could potentially lead to new obesity treatments. “In summary, we show that LEP resistance in DIO animals is caused by increased mTOR activity in POMC neurons and that RAP reduces obesity by re-sensitizing endogenous LEP signaling in these cells,” the authors wrote. “These findings thus have important implications for our understanding of the pathogenesis of obesity and potential therapeutic applications.”
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. “Reversing LEP resistance could also have clinical implications, particularly because LEP spares lean body mass in contrast to the new peptide-based therapeutics that can cause significant loss of lean mass,” the scientists pointed out.
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.
“The development of brain-specific rapalogs provides a possible means to selectively reduce mTOR activity in the brain, and it might also be possible to develop cell-specific mTOR modulators,” the investigators noted. “Alternatively, the development of means for cell-specific delivery of RAP to POMC neurons could provide new avenues for treating obesity or maintaining weight loss.”
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