The human body operates through a complex network of interconnected systems, each influencing the others to maintain equilibrium. One crucial example is the signaling pathway where fat cells release a molecular message in response to food intake, promptly informing the brain of satiety. This signaling relies on the hormone leptin and is essential for regulating appetite and body weight. Given this intricate regulation, the question arises: why do individuals still gain weight with age, and why is weight loss so challenging despite caloric restriction?
The Role of Leptin Resistance
In many cases, the answer lies in leptin resistance, a disruption in communication where the brain ceases to respond to the satiety signal. Even when leptin levels are elevated, the brain fails to register the signal, leading to overeating and hindering sustained fat loss. Leptin resistance is prevalent in individuals with obesity and is also associated with aging, particularly the accumulation of abdominal fat, which can impair leptin sensitivity even in those with a stable body weight.
Leptin resistance is not merely a characteristic of obesity but also a consequence of aging. Recent research in mice suggests a potential strategy for restoring leptin sensitivity and rebalancing appetite control, focusing on rapamycin. Rapamycin is a drug known for its ability to slow aging and extend lifespan in animal models. This article explores how rapamycin may reactivate the brain’s response to leptin, leading to reduced food intake, lower fat mass, and new possibilities for treating obesity and age-related metabolic dysfunction.
Rapamycin: An Anti-Aging Drug
Rapamycin gained recognition as an anti-aging treatment following a 2009 study in Nature that demonstrated its ability to increase the lifespan of older mice. In this study, mice began rapamycin supplementation at 600 days old (equivalent to approximately 40-60 years in humans) and lived up to 52% longer (from day 600 until death) compared to mice not receiving rapamycin (5-16% increase in total lifespan). Over the past 15 years, extensive research has shown improvements in immune, cardiovascular, neurocognitive, and skin health in humans. While the impact of rapamycin on other systems has not been thoroughly examined in humans, its potential benefits in mice extend to numerous organ systems and have even shown promise in the treatment of several types of cancer.
Rapamycin's unique ability to influence multiple hallmarks of aging sets it apart from other interventions. It improves mitochondrial efficiency, supports stem cell maintenance, slows cellular senescence, and reduces the pro-inflammatory secretions that accumulate in aged tissues. These far-reaching effects have established rapamycin as a closely studied pharmacological tool in longevity science.
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Rapamycin extends lifespan by modulating multiple hallmarks of aging, including improvements in mitochondrial function, support for stem cell maintenance, attenuation of cellular senescence, and suppression of pro-inflammatory secretions associated with senescent cells. The convergence of these effects has positioned rapamycin as one of the most extensively studied pharmacologic agents in the field of aging biology.
New evidence published by Dr. Jeffrey M. Friedman in Cell Metabolism identifies a new mechanism-leptin resistance-by which rapamycin improves the body’s ability to sense nutrient availability and enhance health and longevity. Leptin, a hormone released by the stomach and white adipose tissue (fat cells) in the abdomen, signals fullness to the brain upon food consumption. Leptin function is critical for maintaining energy balance and preventing overeating. However, in obesity and increasingly with age, leptin’s signal becomes distorted, and despite high circulating levels of the hormone, the brain stops responding appropriately. This loss of leptin sensitivity can make maintaining a healthy body weight and preventing excess belly fat accumulation more challenging.
This article reviews Dr. Friedman’s research from Princeton University, which demonstrates how rapamycin reduces food intake and fat mass in mice with obesity fed a high-fat diet. Additionally, it examines the mechanisms within the brain responsible for rapamycin’s restoration of leptin sensitivity and reversal of obesity.
Leptin, Leptin Resistance, and Obesity: A Detailed Look
Leptin, released by the stomach and abdominal fat cells in response to food intake, functions as part of a negative feedback loop that regulates appetite and prevents overeating. Leptin secretion from the stomach helps regulate short-term appetite immediately after a meal. In contrast, leptin secreted by abdominal fat cells is stimulated by rising insulin levels following a meal, contributing to longer-term appetite regulation.
After crossing the blood-brain barrier, leptin binds to receptors in the arcuate nucleus (ARC) of the hypothalamus. There, it activates neurons that produce proopiomelanocortin (POMC), a precursor to smaller signaling molecules, including alpha-melanocyte stimulating hormone (α-MSH), which binds to MC4R receptors to suppress appetite and stabilize body weight.
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Leptin enters the brain and triggers a chain reaction that suppresses appetite and helps us better recognize fullness during a meal. In healthy individuals, this signaling chain works seamlessly. Leptin enters the brain, activates the POMC-α-MSH-MC4R pathway, and helps shut down hunger, both in the short term and over the course of several hours, as part of a tightly coordinated feedback loop that keeps food intake aligned with energy needs.
However, when this system breaks down, the consequences are profound. In leptin resistance, a condition common in obesity and aging, the brain stops responding to the fullness signal. The POMC pathway becomes increasingly sluggish, and the brain behaves as though leptin were absent, even when it’s present in abundance. The result is persistent hunger, greater food intake, and gradual accumulation of fat, especially in the abdomen.
This dysfunction reinforces itself: more fat leads to more leptin secretion, but the brain becomes even less responsive. While leptin resistance is difficult to measure directly in humans, one consistent marker is that blood leptin levels tend to rise in proportion to body fat, without corresponding decreases in appetite.
Research by Tan and colleagues has provided a cellular and molecular basis for leptin resistance, showing that mTOR, a nutrient-sensing protein complex, becomes overactive in the hypothalamus during obesity and interferes with leptin’s ability to activate the POMC signaling pathway.
Rapamycin restores leptin sensitivity and improves the brain’s ability to recognize the “fullness” signal in mice by inhibiting mTOR in POMC neurons, increasing α-MSH production and MC4R activation to suppress appetite. Improvements in leptin sensitivity from rapamycin treatment reduces total food consumption, body weight, and fat mass in the process.
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Experimental Evidence: How Rapamycin Restores Leptin Sensitivity
To investigate how leptin resistance develops and how it might be reversed, Tan and colleagues compared two mouse models:
- Wild-type (WT) mice: These mice have normal physiology and intact leptin signaling.
- Ob/ob mice: These mice are genetically modified to lack the Ob gene, preventing leptin production. However, they still have functioning leptin receptors and can respond to externally administered leptin.
Each mouse model was fed either a standard “chow diet” or a “high-fat diet” (HFD) consisting of 60% fat. The four resulting groups were:
- Wild-type-chow (WT-C): A control population with normal leptin signaling that remains weight-stable.
- Wild-type-high fat diet (WT-HFD): Mice exposed to a Western diet, developing obesity and elevated leptin levels but becoming resistant to leptin’s appetite-suppressing effects.
- Ob/ob-chow (OB-C): Genetically leptin-deficient mice on a standard diet, prone to obesity due to constant hunger but remaining sensitive to leptin if administered therapeutically.
- Ob/ob fed a high-fat diet (OB-HFD): Leptin-deficient mice fed a Western diet, gaining even more weight than OB-C mice but still responding to leptin injections due to functional leptin receptors.
After 18 weeks, the researchers examined how these groups responded to leptin. Mice on the high-fat diet consumed more calories and gained more weight than their chow-fed counterparts. The sequence of weight gain increased progressively across WT-C, OB-C, WT-HFD, and OB-HFD groups, suggesting that both genetic and dietary factors compound the problem.
When all mice were given daily leptin injections for one week, leptin reduced food intake and body weight in WT-C mice, as well as in both OB-C and OB-HFD mice, confirming their sensitivity to leptin signaling. However, in the WT-HFD group, leptin had no effect. Despite elevated leptin levels, the brain wasn’t registering the fullness signal, demonstrating that diet-induced obesity alone is sufficient to trigger leptin resistance.
Blood samples revealed elevated levels of methionine and leucine in WT-HFD mice, amino acids known to activate the mTOR pathway. Higher levels of these mTOR-activating amino acids correlated with lower leptin sensitivity across all groups. The authors hypothesized that mTOR activation may directly contribute to leptin resistance observed in the WT-HFD group of mice.
Rapamycin's Role in Re-Sensitizing Obese Mice to Leptin
In subsequent experiments, Tan and colleagues focused on wild-type mice fed a high-fat diet (WT-HFD) for 18 weeks, resulting in obesity and leptin resistance. They conducted four experiments to understand the role of rapamycin, an mTOR activation inhibitor, in restoring leptin sensitivity.
In the first experiment, mice fed a high-fat diet for 18 weeks were injected with 2mg/kg rapamycin daily for 10 weeks. Rapamycin decreased daily and total food intake and reduced total body weight and fat mass compared to mice provided a placebo injection.
The researchers then addressed whether rapamycin increases leptin sensitivity. Leptin-resistant mice fed a high-fat diet for 18 weeks were pretreated with rapamycin for 3 weeks, then provided two daily leptin injections for 3 days. Leptin injection decreased high-fat food intake and reduced total body weight and fat mass in mice pretreated with rapamycin, whereas mice lacking rapamycin pretreatment (placebo injection) remained unresponsive to leptin. These results confirmed rapamycin's role in restoring leptin sensitivity.
In the third experiment, researchers controlled for food intake. Mice pretreated with rapamycin after 18 weeks of high-fat diet consumption had their food limited for 5 weeks, equaling total food consumed in mice with and without (placebo) rapamycin treatment. After 5 weeks, all mice were injected with leptin twice per day for 3 days. Despite similar amounts of food consumed, only mice treated with rapamycin and leptin exhibited reductions in food intake and body weight. Total energy expenditure and fat metabolism were increased, and plasma leptin concentrations were reduced in mice receiving rapamycin and leptin.
Lastly, researchers switched the food consumed by the WT-HFD after 18 weeks from high fat to the standard, well-balanced chow for 4 weeks. As expected, body weight and fat mass significantly decreased in mice whose diets were switched compared to those whose diet remained unchanged. However, mice receiving rapamycin elicited a much larger reduction in daily and total caloric intake as well as larger reductions in total weight and fat mass compared to mice receiving the placebo injection.
These findings confirm that a high-fat diet induces obesity and results in leptin resistance. Rapamycin appears to restore leptin sensitivity and decrease the amount of leptin secreted by fat cells required to regulate food consumption and facilitate weight loss in mice. The weight lost in response to rapamycin came mostly from decreases in fat mass as opposed to lean mass, helping to preserve muscle mass throughout the intervention. These responses, along with increased overall energy expenditure, suggest that rapamycin may meet the criteria as an effective treatment.
Further Evidence: Rapamycin and Metabolic Improvements
Research has also demonstrated that continuous rapamycin administration to mice concurrently with a high fat, high sucrose (HFHS) diet for 20 weeks resulted in significantly reduced weight gain and adiposity, despite increased or equivalent food intake compared to placebo. The rapamycin-fed mice also demonstrated reduced plasma glucose and improved insulin sensitivity during insulin and glucose tolerance testing. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity.
Since mTORC1 activity is increased in obesity and diabetes, its inhibition in chronic metabolic disease offers an attractive therapeutic opportunity. In rodent models, rapamycin has been utilized to evaluate effects on glucose tolerance with conflicting results so far. Many published studies have clearly demonstrated that rapamycin administration leads to the development of hyperglycemia, increased insulin levels, and glucose intolerance. However, a handful of studies have shown that rapamycin improves glucose metabolism in mice.
These conflicting results highlight the complexity of rapamycin's effects on metabolism, necessitating further research to fully understand its potential benefits and risks.
Rapamycin's Effects on Glucose Metabolism and Insulin Sensitivity
To investigate the effects of chronic mTOR inhibition on insulin sensitivity and glucose metabolism in vivo, Wistar rats were chronically administered for 3 weeks with either Sirolimus (a clinically formulated injectable form of rapamycin) or vehicle. Sirolimus treatment of Wistar rats fed a standard diet resulted in a significant decrease in cumulative body weight (BW) gain from the third day to the end of the experiment, associated with a significantly decreased food intake. Sirolimus induced a significant impairment of glucose tolerance compared with control rats, despite the fact that Sirolimus-treated animals had a lower BW gain and decreased caloric intake, two factors which usually tend to increase insulin sensitivity.
Reversing Leptin Resistance: A Breakthrough Discovery
Researchers have discovered a neural mechanism involved in leptin resistance and identified a way to reverse it in mice using the mTOR inhibitor rapamycin. As the researchers describe in a 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.
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. Leptin-sensitive animals showed no such dysregulation. 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.
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.
Marmoset Study: Metabolic Consequences of Long-Term Rapamycin Exposure
Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. A study found that long-term treatment of marmoset monkeys with orally-administered encapsulated rapamycin resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment. Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment, while liver tissue exhibited suppressed G6Pase activity with increased PCK and GPI activity. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning.