The Da Vinci Code of being overweight

Da Vinciho kód nadváhy

It is naive to think that excess fat can be solved simply by the equation: take in less energy (calories) and expend more energy (exercise). What we eat our cells use up to be at all or as fuel for physical activity.

The total amount of energy that the body uses to ensure all these functions is called the metabolic rate. The amount of energy that the body consumes at rest, the so-called resting metabolic rate (REE) accounts for up to 60-75% of total energy consumption. REE is not immutable, it is subject to an adaptive mechanism by which the body resists the loss of body weight and fat volume. The body compensates for the reduction in caloric intake by reducing REE. Conversely, regular exercise increases REE in part because muscle has a higher metabolic activity than fat. When energy intake exceeds total energy needs, insulin and other metabolic regulators trigger nutrient uptake and storage.

Tissues such as the liver and muscles have a limited capacity to store glucose in the form of glycogen. BUT, adipose tissue has an essentially infinite capacity to store excess energy as fat. When the energy supply is lower than the body's needs, fat stores remain intact until all glucose is used up. Genetics play an important role in weight management.

For example, changes in genes that affect the function of leptin receptors increase susceptibility to obesity. Unlike the genetic code, which is for the most part immutable, the effect of diet and lifestyle can change the behavior of genes. Such changes can be transmitted to offspring to a certain extent. Maternal obesity or paternal metabolic diseases can promote obesity and metabolic disorders in children.

What we eat directly determines the genetic messages the body receives. These messages feed back all the molecules that make up metabolism, telling the body to burn calories or conserve them. Molecules produced by our own fat cells wreak havoc on metabolism by increasing inflammation, increasing appetite, slowing fat burning, and increasing the production of stress hormones. Eliminating inflammation helps get rid of fat, and losing fat helps get rid of inflammation. Fat is an endocrine organ that affects the rest of the body, especially the brain in terms of what it has to do with the two most important tasks of life - eating and reproducing. Together, insulin and leptin control the quality of metabolism and, to a significant extent, the rate of metabolism. They are at the peak of metabolic importance in relation to disease. Insulin mostly works at the energy level of the individual cell.

Leptin (secreted by adipose tissue) controls the energy storage and consumption of the entire "republic of cells" by allowing the body to communicate with the brain about how much energy (fat) the republic is storing, whether it needs more or should burn some, and whether it is an advantageous time (from a dietary perspective ) for the republic to multiply or not. The main function of fat is to store fatty acids and other fats during periods of excess energy and release them for energy production during times of starvation.

Adipose tissue enlarges and remodels in response to calorie intake. Under healthy conditions, excessive caloric intake causes an increase in the number of fat cells and increases their response to insulin. Under unhealthy conditions, especially when excessive caloric intake is continuous, fat cells get bigger because they accumulate more fatty acids, but their number decreases. These enlarged fat cells become less and less responsive to insulin and release more and more inflammatory signals that start and perpetuate a cycle of tissue damage and chronic inflammation. Perhaps the best-known signals are leptin and adiponectin. Healthy conditions are such that the inflammation-inducing effect of leptin is balanced by the anti-inflammatory effect of adiponectin. High levels of leptin and low levels of adiponectin are associated with obesity.

With increasing kg, fat cells (adipocytes) pump more and more leptin into the circulation to tell the brain that the fat reserves are sufficient. Because the same adipocytes are constantly "washed" with excess leptin, they lose the ability to respond to leptin. Leptin increases tissue sensitivity to insulin, promotes thermogenesis, increases glucose uptake by cells and lowers blood fat levels. Importantly, leptin also suppresses hunger. As part of an evolutionary defense against excessive fat loss, leptin release decreases with decreasing fat mass. Unfortunately, this adaptive mechanism interferes with healthy weight loss in overweight and obese people. Despite the high production of leptin in response to overeating, the response to leptin is attenuated (in subjects with obesity and impaired insulin function), so that high levels of circulating leptin lose their effect on appetite and maintaining a healthy metabolism.

In particular, adipocytes and neurons alike lose their ability to respond to leptin signals due to the binding of CRP (inflammation) to leptin, which has two harmful consequences: fatty acid oxidation (fat burning) in adipocytes decreases significantly and their ability to absorb free fatty acids (fat) from the blood decreases . Inflammation significantly impairs leptin's ability to control weight. Inflammation (CRP/ TNF-α) influences the relationship of circulating leptin to atherosclerosis (calcium content in coronary vessels) in overweight and obese individuals.

Restoring leptin signaling normalizes body weight and metabolic disorders, including impaired insulin function. Leptin is able to increase the production of CRP (it is produced by liver cells and cells of the vascular lining) and at the same time their mutual interaction is a reflection of body fat content. In turn, CRP binding to leptin impairs its physiological function, especially leptin's ability to stimulate AMPK (...reduced production of NO, cGMP). A higher than optimal CRP level is associated with impaired glucose consumption (insulin resistance), fat storage (and increased triacylglycerol/fat content). Additionally, excess leptin can promote inflammatory damage to the gut.

Our internal clock - the circadian cycle affects every biological system of our body, including metabolism and body weight. The central part of the brain is affected by day and night cycles, but the circadian system of external tissues responds to temperature, the effect of hormones, neurotransmitters, certain nutrients, the intake and intensity of sleep, food and physical activity. Sleep disturbance, exposure to light at night, jet lag, nocturnal activities and eating impair the synchronization of this regulatory network, which disrupts the energy balance in relation to weight gain and metabolic disturbances. For example, leptin, which suppresses appetite and increases thermogenesis, is highest at night. So, conditions and behaviors that disrupt the circadian cycle make it difficult for leptin to function and contribute to a loss of energy balance.

Daily rhythms, overeating and eating at night disrupt the composition and activity of the microbiota. When you add to that the impaired function of the intestine (inflammatory damage...high leptin) you are "after sleep" and gain weight. Weight gain is an effect of reduced thyroid function and can also be its cause. Slowed metabolism and weight gain leads to an effort to reduce food intake. A reduction in caloric intake can reduce the level of the active hormone (triiodothyronine, T3), which will be reflected in a slowing of the basal metabolic rate and even greater fat gain.

There are two main types of adipose tissue: white and brown. Brown adipose tissue is made up of fat cells that are rich in mitochondria and are specialized for heat generation (thermogenesis), while white adipose tissue cells are more involved in metabolic activity. A third type of fat cell has recently been discovered. These newly identified fat cells, known as beige or so-called brite cells, appear to be more flexible in their function and are able to increase their thermogenic activity (energy consumption) through a process known as browning. The "fight or flight" aspect of the nervous system, such as exposure to cold temperatures and extreme physical stress, increases the size and activity of brown adipose tissue and stimulates the browning of white adipose tissue.

Hormones including thyroid hormone, insulin, leptin, melatonin have been shown to induce browning. Other factors that may influence browning include diet, fasting, exercise, environmental influence on gene action, and microbiota composition. Not all body fat is created equal. The one on the stomach is a machine of destruction. Deep abdominal fat turns into its own organ and becomes a factory of inflammation. The bigger the fat pack, the more inflammatory chemicals are produced that damage our hardware and provoke further fat gain. The cell continuously adjusts its metabolism to prepare enough energy for its needs depending on the availability of food.

Adenosine monophosphate-activated protein kinase (AMPK) is found inside every cell and serves as the main energy sensor. The level of AMPK activity affects body fat composition and our lifespan. AMPK activation increases energy consumption by burning fat (blocks mTOR, decreases fat cell size), improves glucose removal from circulation. The health of the mitochondria depends on it, and thus the availability of energy necessary for life. It increases the activity of sirtuins. The removal of toxic proteins (beta-amyloid/alpha-synuclein) that accumulate in the aging cell and its power plant (mitochondria) is accelerated. During fasting, AMPK increases, which slows down cell reproduction and promotes efficient use of stored fat. Aging cells suffer from reduced AMPK. AMPK decline is heavily involved in degenerative aging.

The modern population consumes excess calories and suffers from chronic suppression of AMPK activity. This can result in cancerous cell transformation, accelerated aging and excessive fat storage. I think that healthy weight loss first of all requires a complex "rebuilding of the head" in relation to regular physical activity, intensity and frequency of diet, sleep, activities that make a person happy and experiencing problematic phenomena. Second, 100% thyroid fitness is required. In the part of restoring the balance of metabolism (the ability to create energy, inflammation, metabolic signals), we will prepare a solution that can be easily implemented in a short time.

- Peter Szalay, ioy biochemist.

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