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New research reveals a surprising link between mTOR inhibition and the prevention of obesity and metabolic dysfunction. This complex story of mTOR's involvement in metabolic disorders unlocks new insights into the link between mTOR and obesity, and raises the potential for mTOR inhibitors like rapamycin to play a crucial role in preventing and treating these conditions.
By: Dr. Sarah Ahmed
Metabolic syndrome is an umbrella term for a cluster of risk factors that can lead to cardiovascular disease. Some of these risk factors include abdominal obesity and high blood pressure. As we age, we can be at risk for metabolic syndrome. One factor that contributes to metabolic syndrome is our nutritional intake. If we consume a diet that is high in processed foods and excess calories on top of a sedentary lifestyle, we are at an increased risk for obesity and diabetes.
When we eat a diet with excess nutrients, our bodies respond by ramping up a pathway called mTOR. The mTOR pathway is responsible for regulating cell growth and replication. You can think of mTOR as the air-traffic controller for cellular growth. When a cell is exposed to growth stimuli or an excess of nutrients, mTOR coordinates cellular protein synthesis and cell growth.
Conversely, when nutrients are scarce, mTOR coordinates the cell's autophagy machinery to recycle cellular debris and convert it into cellular energy to compensate for the lack of nutrients. This process of autophagy is the cell's built-in programming to preserve energy in states of nutrient deprivation while simultaneously creating a cellular 'deep cleaning' phenomenon.
mTOR can be dysregulated by persistent overeating. When nutrients are persistently abundant, mTOR overactivity can lead to the growth and replication of fat cells, also known as adipocytes. This is problematic because excess adiposity is linked to a variety of health issues, including obesity and diabetes.
The hyperactivity of mTOR driven by overeating not only accelerates fat cell accumulation and growth but also drives insulin resistance and metabolic dysfunction.
Insulin and insulin-like growth factor 1 (IGF-1) are two hormones that play important roles in regulating cell growth, metabolism, and aging. When insulin or IGF-1 bind to their respective receptors on the surface of a cell, a cascade of signaling events is initiated that ultimately leads to the activation of the mTOR pathway. Once activated, mTOR promotes cell growth and proliferation by stimulating protein synthesis and other anabolic processes, which in excess can grow unhealthy tissue and promote the proliferation of dysfunctional senescent and cancerous cells.
This close relationship between insulin/IGF-1 and the mTOR pathway has important implications for a wide range of diseases and conditions. In terms of metabolic health, persistently high levels of these hormones can amplify metabolic dysfunction.
When we consume excess nutrients, our insulin is constantly spiking, thus sending signals to activate the mTOR pathway. It's important to remember that as we become insulin resistant, it requires more insulin to store the same amount of glucose, which means higher insulin levels amplify mTOR activity.
The more we consume, the more active our mTOR pathway is in growing the number and size of fat cells. These adipocytes accumulate, leading to unwanted weight gain and increased risk for obesity-related health issues such as diabetes and heart disease.
When we consume excess nutrients, the mTOR pathway activates and triggers a cascade of events that ultimately produce fat cells or adipocytes. One key player in this process is a transcription factor called PPAR-gamma, which is activated by the mTOR pathway.
The mTOR pathway and PPAR-gamma are interconnected in a complex and multifaceted way. mTOR is known to activate PPAR-gamma, which in turn regulates metabolism and is a key factor in the process of adipogenesis or the formation of fat cells. When nutrients are abundant and mTOR is active, this leads to an increase in PPAR-gamma activity, which in turn promotes the growth and replication of adipocytes.
mTOR hyperactivity and dysregulation are strongly correlated with insulin resistance and pancreatic beta cell function loss. When we consume excess nutrients, our beta cells must work overtime to produce insulin to regulate our blood glucose levels. However, if this excess demand continues for too long, these cells can become exhausted and eventually die off, leading to insulin resistance and type 2 diabetes.
In a recent study, a team of researchers set out to explore the impact of inhibiting the mTOR pathway on key indicators of metabolic dysfunction. The team inhibited mTOR in Drosophila to see the effect on fat cell accumulation and insulin resistance. The results were fascinating. mTOR inhibition prevented the increase in triglycerides in their body and also prevented insulin resistance. These results show that, theoretically, in humans, reducing the mTOR pathway can protect against obesity in individuals who consume a high-calorie diet.
Researchers then removed TOR complex-1 (torc1) in the Drosophila adipose tissue to investigate the role of this pathway in the development of obesity.
mTOR is composed of two units, complex-1 and complex-2. The significance of TORC1 lies in its central role in coordinating cellular responses to changes in environmental conditions, particularly nutrient availability. When nutrients are abundant, TORC1 becomes activated and promotes cell growth and proliferation, whereas when nutrients are scarce, TORC1 activity is suppressed, and cellular resources are redirected toward maintenance and repair processes. When we discuss mTOR as a driver of cellular growth, we specifically refer to the work of TORC1.
The study showed that removing TORC1 in adipose tissue prevented obesity in the Drosophila receiving a high-calorie diet. These results suggest that adipose is a critical site for mTOR to mediate its effects. The importance of mTOR in health and disease has led to significant interest in developing drugs that target this pathway, particularly for treating cancer and age-related diseases.
Rapamycin is a drug shown to target the mTOR pathway, specifically by inhibiting TORC1. This has led to significant interest in its potential as a therapeutic intervention for a wide range of diseases, including obesity and diabetes.
One of the critical ways rapamycin may be effective in treating these conditions is by reducing the number of fat cells accumulated in our bodies. As we discussed earlier, TORC1 plays a critical role in the formation and accumulation of fat cells. By inhibiting this pathway, rapamycin may be able to prevent or reduce fat cell growth.
Moreover, accumulated fat in our bodies has been linked to the generation of reactive oxidative species (ROS) and oxidative stress. This can lead to cellular damage and dysfunction and has been implicated in the development of a wide range of diseases, including diabetes.
By reducing the number of fat cells and potentially decreasing oxidative stress, rapamycin has the potential to be a powerful tool for regulating metabolic dysfunction. Indeed, recent studies have shown that adding rapamycin to current gold-standard therapies for diabetes can help reduce oxidative stress and improve metabolic outcomes.
Metformin is already a first-line drug used in the treatment of diabetes. Metformin reduces the production of glucose by the liver. It also increases insulin-dependent glucose uptake and promotes fatty acid usage in our peripheral tissues, all of which lower fat mass.
Combining metformin and rapamycin can increase our body's sensitivity to insulin and combat aging by fighting against oxidative stress produced by our fat cells and reducing the number of fat cells. In theory, if the hyper-activation of mTOR can cause metabolic syndrome, obesity, and diabetes, then a drug like rapamycin, which blocks the activity of mTOR, can reduce our chances of accumulating fat and diabetes.
Combining metformin with rapamycin has the potential to be a powerful therapeutic intervention for a range of metabolic disorders, including obesity and diabetes. One of the key benefits of this combination therapy is its ability to increase our body's sensitivity to insulin, which is crucial in maintaining healthy blood glucose levels and in turn reducing oxidative stress. By reducing the number of fat cells and fighting against oxidative stress produced by these cells, the combination of metformin and rapamycin can potentially reduce the risk of developing metabolic syndrome, obesity, and diabetes.
Moreover, rapamycin has been shown to have anti-aging effects, in part due to its ability to reduce oxidative stress and inflammation. By combining metformin and rapamycin, researchers are exploring the potential to combat aging and age-related diseases, such as Alzheimer's and cardiovascular disease.
Although the combination therapy of metformin and rapamycin holds promise in improving healthspan when used in conjunction with lifestyle changes such as diet and exercise, it's important to stress that these medications are not intended to be used for weight loss. Lifestyle changes, such as a healthy diet and regular exercise, remain the most effective ways to target obesity and related metabolic disorders. The most important way to prevent systemic and persistent mTOR hyperactivity is to avoid overeating.
Nonetheless, the combination of metformin and rapamycin represents an exciting avenue for future research and the development of new therapies for metabolic disorders and age-related diseases.
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