Dr Aidin Rawshani

Obesity and overweight: causes, risks, and diabetes

Contents

What is obesity and excess weight?

Obesity (obesity) is a disease that affects millions of individuals around the world. Obesity and overweight are conditions associated with an increased risk of serious age-related diseases such as cardiovascular disease, type 2 diabetes, high blood pressure, elevated blood lipids, reduced sugar tolerance, liver greasing, obstructive sleep apnea, cancer, and several other diseases.

Population studies estimate that the prevalence of obesity and overweight continues to rise among all social classes, ethnic groups, age groups, and both sexes. The World Health Organization (WHO) estimates that 1.9 billion people suffer from overweight and about 650 million of them suffer from obesity.

In this article, we will discuss various concepts that are important to know. The World Health Organization (WHO) has developed international indicators of overweight and obesity called the body mass index (BMI). The measure is based on the ratio of height to weight. You can calculate your BMI by dividing your body weight into kilograms by its height in meters squared.

For example, a person weighing 75 kg and 1.70 metres tall has a BMI of 26 kg/m2 (75 kg/(1.70 x 1.70) = 26 kg/m2).

Causes of overweight and obesity

A simple explanation model for the development of obesity and overweight is that there is an imbalance between the intake of calories and the consumption of the body’s energy, but according to this model, obesity is the result of low physical activity (sedentary lifestyle) and overconsumption of foods with high energy levels, in reality, the biological mechanisms behind the development of obesity are more intricate.

Risk factors

Several factors interact in the development of obesity, such as socioeconomic factors (income, education and marital status), stress, lack of sleep, mental illness, age, ethnic origin and factors such as the environment, personality type, eating habits and heredity (genetics).

Basal metabolism and energy balance

Basal metabolism is the number of calories that your body burns to produce energy for your body, even when you sleep. This energy is used to support several vital functions and organs of the body, as well as to maintain body temperature.

Thermogenesis

We, humans, burn our fat deposits at various speed in the body. In addition, we have different conditions to convert excess energy into body heat (thermogenesis), the body’s ability to produce heat is of great importance for the whole metabolism. There are three variants of thermogenesis in the body.

  • Training Related Thermogenesis
  • Non-Exercise Thermogenesis
  • Diet-induced Thermogenesis

Basal metabolism (Basic metabolic rate)

Your body also needs energy constantly to ensure that you have the right amount of fluids and essential substances for metabolism. For example, your nerves and muscles can not work without a specific concentration of two important minerals called potassium and sodium (electrolytes). Monitoring and regulation of these two minerals account for about 20 to 40 percent of the energy used when resting, according to the Linus Pauling Institute.

Several factors affect your basal metabolism. Some people have a higher “metabolic rate” thanks to their genes. Muscles burn three times more calories than fat, even when you sleep, so the percentage of muscle compared to fat changes your metabolic rate. Age makes a difference because the body loses muscle mass with aging (sarcopenia), which reduces metabolism.

When you’re not consuming enough calories to support your minimum energy needs, your metabolism decreases by up to 30 percent. A fever increases the body’s metabolic rate by 7 percent for every 0.5 degrees Celsius above normal body temperature. When the thyroid gland does not produce the right amount of hormones, the metabolism can drop by 30 to 40 percent.

You can calculate your basal metabolic rate by following a formula based on height, weight and age, but it only gives an estimate. To get the exact speed, you need to consider all your individual factors, use special equipment and get measurements under strict conditions, for example, after a good night’s sleep and while fasting.

The basal metabolic rate accounts for only about 70 percent of the calories used by your body. The total amount of energy you burn is determined by your basal metabolic rate plus the amount of physical activity that you add and the calories that burn when you digest food and absorb nutrients.

Body mass index (BMI)

BMI is the most common anthropometric measuring instrument but at the same time quite inadequate. BMI is a rough estimate of fat content and does not distinguish between different types of fat, fat localization, fat mass and lean body mass. Therefore, 5 BMI should not be used to estimate BMI in bodybuilders or athletes.

For people older than 70 years, a higher BMI appears to be associated with a lower risk of disease. BMI is not used for children. Instead, a measure called ISO-BMI is used, which, in addition to weight and height, also takes into account the child’s age and height growth.

Two important factors that are not incorporated in BMI are age and gender. The main reason why BMI is used in clinical contexts is probably that BMI is easy to measure and has therefore been used in large international research studies.

A BMI between 18.5 — 25 kg/m2 is considered normal weight, a low BMI of less than 18.5 kg/m2 is also not healthy and is called underweight. BMI between 25 — 30 kg/m2 is considered to be overweight, BMI above 30 kg/m2 is considered to be obesity and severe obesity is considered to exist when BMI ≥ 40 kg/m.2,6

Various measurement methods that estimate the amount of body fat

Some doctors suggest that you should supplement your BMI with waist circumference, which is another marker for obesity and overweight. Waist circumference is a better marker for determining whether the fat mass is visceral or subcutaneous obesity.7 As mentioned earlier, visceral abdominal obesity, i. e. the one surrounding the abdominal organs, is more dangerous than the subcutaneous obesity placed under the skin.

A high waist circumference suggests that the person has a significant proportion of visceral obesity that is around our important abdominal organs and, in addition to their metabolic effects on these organs from a closer distance, most likely, the fat cells that are in the abdomen are more metabolite active than the fat cells under the skin.

Several methods have been designed to assess whether an individual has unhealthy amounts of body fat and whether it is in particularly dangerous locations. These are based on anthropometry and bioelectric impedance analysis (BIA), which is a method that measures how much current passes through the body with various measuring tools to estimate the amount of muscle mass, fat and skeleton in percentage points. All these tissues have different build-ups and therefore current passes different forts through the tissues, this is recorded and measured to determine what the body consists of. Other methods are called densitometry (DXA, bone densitometry) and there are more advanced methods based on radiographs.

What factors regulate your body weight?

To describe the factors that regulate body weight, we first simplify the model by describing three main factors: energy intake, energy expenditure and how the body stores fat. These systems interact continuously and are regulated by several organs in the body, among other things, this is regulated by the brain and our hormones.1

Dozens of factors affect the above-mentioned processes, such as the environment, lack of sleep, shift work, temperature, diet, physical activity, genetics, the bacterial flora of the intestine (microbiota), drugs, substances affecting hormones, and the period when the fetus grows in the womb (embryonic period).

A challenge with population studies aimed at investigating the effects of obesity and overweight is the prevailing heterogeneity in individuals with obesity around the world.

Fatty tissue is divided into different parts of the body and can be divided into different groups depending on location and characteristics. Fat accumulation under the skin is known as subcutaneous fat and occurs most often around the hip and thigh, subcutaneous fat is what appears on the outside of the body and is more common in women.

Different variants of body fat

Another variant of fat is visceral fat that accumulates around vital abdominal organs, such as the liver, stomach, pancreas and intestines. Abdominal obesity (visceral obesity) is more common in men and tends to be more unhealthy, especially for the development of cardiovascular diseases, type 2 diabetes and metabolic syndrome.

A third variant of fat is ectopic fat that accumulates around our blood vessels, the heart and other organs where their high metabolic activity has a negative impact on the organ they surround. Various factors affect the development and movement of fat cells.

The prevailing hypothesis is that when the energy balance is positive, i.e. that the body receives more energy than it does, the fat tissue first accumulates under the skin (subcutaneous fat), when the metabolic state worsens and the energy levels become too high and that the space under the skin becomes insufficient for The fat cells move the most metabolic active fat cells to other parts of the body, most likely to the abdomen first and then become visceral abdominal obesity, some believe that the most metabolite active fat cells from the visceral abdominal obesity then move to blood vessels and heart where it becomes to ectopic fat. The factors that activate these processes are currently unknown.

The link between obesity and the environment

Chronic diseases and obesity appeared as leading health problems only in this century, most likely due to several factors, such as urbanization, unhealthy diet, refined carbohydrates, sedentary lifestyle, reduced physical activity, stress, exposure to chemical pollution and lack of sleep.

Infectious diseases, which were the main cause of premature deaths in the 20th century, do not exist to the same extent in developed developed countries and studies show that life expectancy has increased by almost 30 years since the 20th century.

There are several factors that lead to a positive energy balance and weight gain, in recent decades, increased access to food, increased consumption of food per household, less physical activity and more sedentary activities have led to a sharp development of obesity and overweight.

In the United States, authorities estimate that the nutritional content of food has changed dramatically over the last few decades. Currently, people in Western countries eat more carbohydrates and fats than we have ever done before, soft drinks and larger portions of food also contribute to the growing obesity epidemic. Several medicines also have weight gain as a side effect, especially medicines for psychiatric disorders, but these cases represent a minimal proportion of the obesity epidemic.

At the same time, the development of industrialized communities has contributed to a reduction in mortality from several different diseases, such as infectious diseases. As the incidence of infectious diseases decreased, life expectancy increased and instead increased the incidence of age-related diseases, these are now called chronic diseases, such as cancer, cardiovascular diseases, type 2 diabetes, dementia and obesity.

The energy metabolism of the body

We humans have different approaches to regulate body weight and energy levels over long and short periods of time. This the body succeeds in despite constant variations in the number of calories that we consume and the amount of energy that we spend. Our genome and environment interact in a complex system that regulates several different physiological processes in the body.8.9 The organs involved in this system are the brain, the bacterial flora of the gastrointestinal tract, fatty tissue, stomach, pancreas and other hormonal organs.9

The brain regulates metabolism and energy balance in the body

The areas of the brain that regulate these mechanisms are mainly two regions called the hypothalamus and the hippocampus in medical language. Other areas of the brain also participate in the regulation of energy balance but do this by registering and modifying hedonic memories of different foods, this process gives rise to positive and negative memories associated with different foods.9 Hypothalamus has the task of sending signals through the involuntary nervous system (autonomic nervous system), but also through hormones to maintain energy balance.

The signals sent out regulate metabolism in organs such as the heart, kidney, liver, adipose tissue, skeletal muscle and pancreas. A hormone called Leptin is believed to be responsible for the initiation and regulation of this signaling system in the hypothalamus. In obesity and type 2 diabetes, the body becomes worse at recording energy levels in the body and signaling these levels to the brain, a major contributor to impaired control of energy levels is insulin resistance. The body does not perceive that reserved energy levels are very high and therefore continues to accumulate excess energy as adipose tissue.

Research shows that mutated variants of the hormone Leptin can cause severe obesity and are to some extent treatable with injections of the hormone Leptin (Myalept, metreleptin). However, the majority (95%) of individuals with obesity and type 2 diabetes have no mutated variants of the hormone Leptin but rather elevated levels of Leptin (hyperleptinaemia), research shows that individuals with overweight, obesity and type 2 diabetes have reduced sensitivity to Leptin in adipose tissue and brain, just as when the body develops insulin resistance.

Thus, leptin resistance in adipose tissue, brain and other organs, just like insulin resistance is a central factor in the development of obesity and type 2 diabetes. Reduced food intake or increased physical activity leads to a negative energy balance and a cascade of compensatory mechanisms that preserve vital functions but burn (oxidize) stored energy mass, especially adipose tissue to maintain the body’s energy needs.10

The body’s ability to save energy in the form of fat tissue or sugar deposits in muscle cells and other organs is shown to be different in people with overweight and obesity. Some studies suggest that obesity is associated with an increased ability to preserve the body’s excess energy.

Negative energy balance

Research studies have shown that people with a negative energy balance experience several positive physiological processes in the body even though it is not so clearly visible on body weight. Negative energy balance means that the body consumes more energy than we supply the body with, this results in the breakdown of adipose tissue and sugar stores to provide the body with energy.11

The physiological changes that occur in various organs including the brain during weight loss persist even while the individual maintains weight loss, it is unclear what the implication of these mechanisms is in individuals who no longer have excessive fat mass. Physiological and metabolic changes that have arisen are not similar to those seen in individuals who have never been overweight.11

Presence of obesity and overweight

According to WHO, 2 billion adult individuals suffering from obesity or overweight, of which approximately 650 million are estimated to suffer from obesity. A number of studies show that obesity is more common in women while overweight is common in men, other studies have observed similar conditions. Studies from the United States show that African-Americans have a higher incidence of severe obesity compared to other ethnicities.12 Asian populations have an average lower BMI than Caucasians from Western countries, but Asians have a greater propensity to develop the dangerous variant of abdominal obesity (visceral obesity) which contributes to the fact that they develop type 2 diabetes at lower BMI levels compared to individuals from Western countries.13

How common are obesity and overweight?

The incidence of obesity has increased gradually since 1970 and by 2030 it is estimated that approximately 3.3 billion people will have BMI 25 kg/m2 or higher.14.15 In several countries beyond North America and Europe, the number of adults with obesity and overweight is expected to exceed the number of adults with normal weight. Studies show that the negative health effects of obesity pose a greater threat to public health than hunger and malnutrition. Several trend analyses for overweight and obesity in minors in North America and Europe demonstrated that the prevalence (prevalence) of obesity stabilized in recent years, but the number of childhood obesity is still too many. What factors affect individual metabolism (metabolic imprinting)

Meaning of obesity during childbearing years

In all individuals, critical periods exist during the childbearing and adolescence period that determines to some extent the development of adipose tissue and its future characteristics and destiny. Metabolic imprinting is the programming that each individual’s metabolism (metabolism) undergoes during fetal development and childbearing years.16 These genetic (as well as epigenetic) changes have a permanent influence on future disease risk and health. Research shows that excessive weight gain in the mother during pregnancy (prenatal period). Sharp changes in body weight during the first 20 weeks of pregnancy have proved to be especially important for the development of excess weight in the child in adolescence.

Birth weight is a useful surrogate marker of fetal nutrition, both overnutrition and malnutrition during fetal life can lead to obesity later in life.17.18 A high birth weight has been associated with a higher risk of obesity, while a low birth weight has been associated with a higher percentage of body fat, regardless of BMI and more visceral abdominal obesity in adulthood.19

In infants, it has been observed that rapid weight gain increases the risk of overweight later in life. The nutrition consumed by the mother during pregnancy and during the lactation period can cause metabolic complications for the baby in the future.20 Longer lactation period has been associated with a lower risk of overweight later in life,21 the reason for this is unknown.

Adolescent years are a period of development that is particularly sensitive because hormonal changes lead to faster growth of various organs and several other body tissues leading to, among other things, stronger production of adipose tissue. Research has also shown that the onset of puberty may affect the risk of obesity, that the onset of puberty at an early age is associated with obesity later in life.22

Risk factors

The main drivers for the sudden obesity epidemic are large food intake and a sedentary lifestyle. As we mentioned earlier, a positive energy balance for a longer period causes weight gain.

Genetics about obesity, overweight and diabetes

The search for specific genes that cause obesity has resulted in the identification of various genes that are strongly associated with the development of obesity and overweight. Mutations in a gene called MC4R lead to disturbed satiety and appetite levels, the mutation in this gene accounts for 2-5% of the obesity epidemic and causes severe obesity in early adulthood. The gene is responsible for creating a protein called the melanocortin-4 receptor, the protein is found in the part of the brain called the hypothalamus but also in the adipose tissue.

Another known gene associated with obesity development is the FTO gene that sometimes undergoes mutations, mutation in this gene causes overexpression of two adjacent genes (IRX3 and IRX5) in our genome, thus mutations in these two genes occur secondary to mutation in the FTO gene, it is Thus, the IRX3 and IRX5 genes that contribute to the development of obesity.

The human body has three different types of fat cells, these fat cells are named after their appearance in a microscope and are therefore called white, brown and beige fat cells. In the case of overactivation of these genes, brown adipocytes (brown adipocytes) are converted into a more unfavorable type of adipose tissue, namely white adipocytes. The number of brown adipocytes (brown adipocytes) decreases and the body gets rid of its ability to burn energy by producing “biological heat” that keeps the body warm (thermogenesis), and the body also gets worse at handling elevated levels of blood lipids (lipids).

Individuals with normal weight and overweight have a higher proportion of white fat cells than brown fat cells. It was quite recently that adult individuals even have brown fat cells. Individuals with mutations in these genes constitute a small minority of all individuals with obesity, which explains why the prevailing obesity epidemic is not due to genetic change (genetics). It is more likely that obesity results from an interaction between genes that makes one more susceptible to the development of obesity and different lifestyle factors.

In the text paragraph below, we describe in more detail the relationship between our genome (genetics) and these diseases.

A good diet

A high-quality diet is defined as a balanced diet of substances in which 10 -20% of energy is obtained from proteins, 30% from fats and 50 -55% from carbohydrates, the diet reduces the risk of development of obesity and weight gain. Consumption of fruits, nuts, vegetables, whole grains and yogurt contributes to positive metabolic improvements and weight loss. Consumption of sugary drinks, chips, French fries, processed meat, commercially baked goods, trans fats, refined grains, fast carbohydrates and added sugars is associated with weight gain and the development of type 2 diabetes.

Studies have shown that the use of complex carbohydrates (carbohydrates that take a long time to process, such as grain bread, cereals and vegetables) and healthy foods with a low glycemic index (GI, a measure of the effects of food on blood sugar levels) reduces the risk of obesity development.23

Complications related to obesity and overweight

Obesity is linked to several diseases and conditions, but the areas of disease that have been studied most extensively for people suffering from obesity and overweight are cardiovascular diseases and metabolic disorders such as reduced insulin sensitivity (insulin resistance), metabolic syndrome and type 2 diabetes. The relationship between obesity and other diseases such as cancer, mental health and cognition.25,26

Research on complications related to obesity

Epidemiological research on obesity-related complications is limited for several reasons. One difficulty encountered in international studies has been to define people with “normal weight” (reference group). Guidelines argue that BMI 18.5-25 kg/m2 is compatible with the lowest risk of obesity-related complications.

A meta-analysis studied material from 189 different countries (a total of 4 million individuals were included) where BMI between 20-25 kg/m2 was associated with a lower risk of death while individuals with BMI 20 kg/m2 had a higher risk of premature death.27 Several international studies investigating the relationship between obesity and the risk of serious complications include individuals from all continents, these studies show repeated positive associations between obesity and age-related diseases.

These complications develop because people with obesity eventually develop insulin resistance, hypertension (hypertension), elevated blood lipids (hypercholesterolemia), metabolic syndrome and type 2 diabetes. Another feared complication associated with obesity and overweight is inflammation.

adipose tissue has a unique ability to produce molecules that attract the immune system and thus obesity causes increased inflammation in the body. Inflammation is extremely important in various biological processes, but the low-grade inflammation that occurs in obesity is likely to lead to cardiovascular diseases, cancer, dementia, type 2 diabetes and several other age-related diseases.

Another meta-analysis based on materials from 195 countries studied changes in the incidence of cardiovascular diseases over 25 years, the study showed that obesity was associated with a 70% increased risk of cardiovascular diseases and 60% of individuals who died from cardiovascular diseases were at least overweight.28 An interesting study demonstrated that sharp fluctuations in BMI were associated with an increased risk of coronary heart disease.29

Underlying biological mechanisms to obesity

As mentioned above, body weight and obesity are determined through a complex interaction between genetics, the environment and psychosocial/socioeconomic factors affecting food intake, energy-burning and fat accumulation through several physiological processes.

How the genome affects the development of obesity

Researchers have investigated the relationship between the genome and BMI, some studies suggest that heredity accounts for 40 -70% of an individual’s BMI. There are eleven rare mutations associated with the development of obesity. Two examples are mutations in the part of the genome responsible for the production of the hormone called Leptin, mutations in this part of our DNA lead to improper production of the hormone. As mentioned earlier, there is another known gene associated with obesity, this protein is called the melanocortin-4 receptor (MC4R).

MC4R is the most common cause of “genetic” obesity and is found in 2 -5% of children with severe obesity.9 Obesity and type 2 diabetes are diseases that are due to mutations in multiple genes (polygenic mutations) .9

Methods used to study our genome

To date, scientists have identified more than 300 locations in our DNA that are associated with obesity, these loci are called in medical language. The research method used to study genes associated with obesity is called GWAS (genome wide association studies).

Nowadays, other methods called WES (exome sequencing) are also used, with WES sequencing only protein-encoding parts of DNA, which makes it possible to identify new molecular targets and improve the predictive ability for future complications and response.

In addition, the environment can influence the expression of genes without modification of the genes, this is called epigenetic wide association studies (EWAS) has the capacity to demonstrate how exposure to different environments can affect metabolism in the future. 30

By studying genetic differences between individuals with obesity and normal weight, researchers can find unique genetic changes that hopefully lead to increased understanding of biological mechanisms that cause the development of obesity, hopefully, this will lead to new methods of treatment and prevention of obesity.

Research on special forms of obesity where single mutations (single mutations) are the cause of obesity development has generated tremendous knowledge about the biology of obesity. By identifying single mutations associated with obesity and then mapping the molecular consequences of the mutation of the individual gene, our understanding of obesity and underlying causes increases, although a small percentage of people with obesity have these mutations.

Studying single mutations was one of the first research strategies for studying hereditary variants of obesity. The results showed that genes encoding the hormone Leptin (Lep) and its molecular receptor (Lepr), the proteins Melanocortin 4 receptor (MC4R) and pro-opiomelanocortin (POMC) regulate body weight by affecting important functions in the brain such as satiety and appetite.

The first gene that GWAS research identified was the talked about FTO gene.31.32 We begin to gradually understand how the FTO gene regulates obesity through regulation of appetite, thermogenesis (heat development in our cells), transformation from white fat cells (white adipocytes) to beige fat cells (beige/brown adipocytes), the process leads to a change from white fat cells to brown fat cells, the process is called adipocyte browning.

Brown fat cells are those that have several health-enhancing functions and make up a small percentage of our total fat mass. As mentioned earlier, mutations in the FTO gene cause overexpression of adjacent IRX3 and IRX5.33 GWAS, in addition to the FTO gene, have identified several other gene variants associated with obesity, BMI and waist-to-hip ratio (WHR). 34.35

Our DNA is sensitive to changes in the environment and various factors in the environment can influence how our genes are expressed, this genetic modification is called epigenetic alterations in medical language. These changes can be inherited further.

Epigenetic changes vary in the body’s cells, tissues and over different periods of time, this makes it particularly difficult to study epigenetic changes. Epigenetic studies have not been able to show that the changes occurring in some genes are the cause of the development of obesity, it is possible that these changes are a consequence of obesity.36

Adipose tissue

The body consists of two types of fat, white adipose tissue (white adipose tissue) and brown adipose tissue (brown adipose tissue), these two fatty tissues play an important role in monitoring and regulating the body’s energy balance.37

Brown and beige fatty tissue

There is also a third type of fat called beige fat cells (beige adipocytes), these mimic brown fat cells to some extent but are more distributed among white adipose tissue as opposed to brown fat cells that are localized around specific regions, for example under our collarbone and scapula.

Brown and beige fat cells have a unique ability to develop heat by producing bio-energy. It is mainly brown fat cells that produce the most body heat (thermogenesis). One reason for this is believed to be a protein called UCP-1 that exists in the wall (membrane) of the structure of the cell (organelle) responsible for producing energy (mitochondria). This protein is found to a greater extent in white, beige but mainly brown fat cells.

The brown fat tissue appears to have an ability to burn larger amounts of energy than white fat cells, i.e. brown fat cells contribute to energy expenditure by increasing the body’s temperature. Multiple biological reactions in the body require optimal conditions for proper activation and functioning. There are plenty of brown adipose tissue in newborn babies and this is localized around the clavicles, heart, kidneys, large body artery (aorta), pancreas (pancreas) and bronchi.

The number of brown fat cells decreases with age but exists in small amounts even in older individuals. In humans, it has been discovered that rising levels of brown adipose tissue are associated with lower levels of BMI (negative correlation) but its importance for the development of obesity is still unknown. Researchers hope that one day will be able to activate brown fat cells via drugs to increase thermogenesis and thus create a negative energy balance and weight loss.

It is still unknown what overactivation of these fat cells would have meant in humans, but strong activation of the body’s energy production is likely to cause some complications.

White adipose tissue

People have mostly white adipose tissue (white adipose tissue), and because fat is considered to be the body’s largest hormonal organ, although some believe that the cells lining the inner wall of the blood vessels are the body’s largest hormonal organ (endothelial cells). The white fat tissue secretes several bioactive substances called adipocytokines and adipokines, these are biological signaling substances that, among other things, lead to low-grade inflammation throughout the body.

Studies have also shown that the location of adipose tissue is crucial to how aggressive the metabolic disease is, many individuals accumulate subcutaneous adipose tissue that is found under our skin and visceral adipose tissue (visceral adipose tissue) located around our abdominal organs especially around the liver and pancreas.

What is ectopic fat?

A third variant of fat cells is raised around important organs in the body such as the heart, kidney, liver and blood vessels, this fat is called ectopic fat and is believed to be more bioactive than subcutaneous and visceral fat. Researchers believe that the ectopic fat produces more energy (higher metabolic activity) around these structures which leads to age-related diseases being more prevalent in these organs. Ectopic fat has got its word from fat settling in the wrong places.

Ectopic fat is formed when the volume of subcutaneous adipose tissue exceeds the body’s capacity to store fat under the skin which is believed to result in the migration of subcutaneous fat cells with high levels of free fatty acids (triglycerides) to other vital organs.

Metabolic and physiological effects in adipose tissue

Fat cells synthesize many hormones and proteins that affect the body, studies show that there is a clear correlation between total fat mass and the rate that proteins and hormones are released from fat cells. The fat cells secrete proteins that have specific properties, which contribute to the activation of the inflammatory system, a particular type of inflammatory cells called macrophages is activated and attracted to the adipose tissue.

Once these cells are attracted to the adipose tissue, they are believed to affect the adipose tissue, a higher percentage of inflammatory cells in adipose tissue is associated with a stronger inflammation.

Fat cells secrete a special type of proteins called adipokines whose function is to attract inflammatory cells to the area. The inflammation seen in overweight and obesity can contribute to insulin resistance, cardiovascular diseases and several other risk factors for cardiovascular diseases.

The burning of special fats (triglycerides) in fat cells leads to the release of free fatty acids (FFA), triglycerides are carried out into the blood to various cells and tissues where they are metabolically useful. The concentration of free fatty acids in the blood is elevated in individuals with obesity, and the amount of triglycerides in the blood reflects the enlarged fat mass of these individuals.

The accumulation of waste products from fat metabolism (e.g. ceramides) is, in fact, toxic by-products that accumulate in the fat cells and lead to fat poisoning (lipotoxicity), an unsustainable environment occurs in the cell (cellular dysfunction) which leads to the death of the cell, a phenomenon called programmed cell death or apoptosis.

Elevated levels of blood lipids (free fatty acids), inflammatory signaling substances (adipokines) and fat poisoning (lipotoxicity) in insulin-sensitive tissues (skeletal muscle, liver, adipose tissue and beta-cell) contribute to the development of what is called insulin resistance, which means impaired signaling and signaling response when cells and various tissues are exposed to the hormone insulin that is vital for human metabolism. Assessment of obesity

BMI is not entirely optimal as a measurement tool for total fat mass and does not distinguish between subcutaneous adipose tissue and abdominal obesity, but BMI is a very strong predictor of cardiovascular risk and easy to calculate. degree of obesity.38

Only when we include the waist-to-hip ratio (WHR) and waist circumference can we assess whether abdominal obesity (visceral obesity) or subcutaneous obesity (under the skin) exists.

Anthropometric factors such as waist to hip ratio and waist-length further strengthen our ability to predict the risk of future cardiovascular disease. When assessing obesity, physicians should also check blood pressure, lipid (lipid status), fasting glucose (FP glucose) and long-term sugar (HbA1c).

More advanced diagnostic methods are based on imaging diagnostics, such as densitometry (DXA, bone density measurement) and other X-ray methods, these methods are primarily used in the research context.

Table 1. Waist circumference and risk of obesity-related complications according to WHO.
 Increased riskSignificantly increased risk
Women≥ 80 cm≥ 88 cm
Men≥ 94 cm≥ 102 cm

Preventive factors against obesity

Healthy eating (DASH diet, Mediterranean diet, RESMENA diet and LCHF) and physical activity usually create a negative energy balance that leads to weight loss. People with obesity should begin lifestyle changes as early as possible, studies indicate that we can begin as early as during pregnancy.

Research on pregnant women with diabetes shows that increased physical activity, improved diet, better blood sugar control and counseling for medical treatment against diabetes during pregnancy to optimize metabolic conditions, led to increased well-being of the fetus. 39

However, studies investigating whether increased physical activity and healthy eating in children 2 years of age have shown that it does not have a preventive effect against future obesity.

Studies investigating the importance of increased education and understanding of diet and exercise and more school sport in adolescence children have shown that this type of lifestyle changes leads to a reduction in the risk of developing obesity in the future.

Several researchers believe that the prevention of obesity requires several methods and points of attack.

Treatment for Obesity

Current treatment for obesity focuses on weight loss via risk-based clinical guidelines where healthcare professionals strive for weight loss and improved metabolic status through lifestyle interventions, dietary changes and exercise as first choice followed by medication or obesity surgery ( Obesity surgery) in selected cases.

Several guidelines have been developed in the United States, the UK, and Europe as a tool for healthcare professionals to treat individuals with obesity. There are large variations in treatment responses and treatment strategies against weight loss and several studies have not been able to demonstrate long-term effects and many interventions may not be effective in maintaining weight loss.

Moderate weight loss, defined as 5 -10% weight loss relative to the initial weight of the person is associated with a clinically meaningful improvement in metabolic risk factors in individuals with obesity.40.41

Weight loss by 5% from baseline weight leads to improved function of the cells that secrete insulin (beta cells) and record blood sugar levels and energy balance in the body. These cells are localized in the pancreas, but 5 -10% weight loss additionally leads to increased sensitivity to insulin in the liver and our skeletal musculature. 42

Studies have shown that individuals with obesity and another condition called impaired glucose tolerance (IGT) treated with intensive lifestyle intervention had an average weight loss of 5.6 kg after 2.8 years of treatment and 58% lower risk for type 2 diabetes.43

Obesity surgery (obesity surgery) results in about 15 -30% weight loss from baseline weight in patients with severe obesity and, in addition, leads to the return of type 2 diabetes in almost all cases.44-46 Individuals who underwent obesity surgery have a much lower risk of death and several metabolic risk factors Improving immediately after the procedure.46

Lifestyle changes

Some lifestyle interventions aim to change the individual’s behavior that hopefully leads to a healthier lifestyle, this is considered an important component for successful weight loss.47 Several factors from everyday life that affect the risk of developing obesity are hunger, increased understanding of the consequences of overnutrition and how certain reward systems in the brain work.

The studies investigating these issues noted that participants lost about 3 kg of body weight on average, behavioral changes were not very sustainable in the long term for the majority of study participants, but a number of study participants responded very well to the treatment and maintained a lower body weight for a longer period.

Diet

Dietary treatment for overweight and obesity has been carefully studied in clinical trials over the last 20 years. Negative energy balance through limited calorie intake leads to weight loss. Most diets developed for the treatment of excess weight and obesity are based on reduced calorie intake. A restriction of 1200 kcal per day for women and 1500 kcal per day for men is generally recommended for weight loss and for preserving weight loss.

Interestingly, people can also lose weight by improving the overall nutritional quality (Mediterranean diet, high-quality raw materials) in their food without a direct energy restriction and this also leads to weight loss.48 In a meta-analysis of which studied many different popular diets, it emerged that low-carbohydrate diets produced a weight loss of 7.25 kg after 12 months compared to 7.27 kg from a low-fat diet. 49

However, there are large individual variations in weight loss between each diet, some individuals can gain weight while others lose weight on the same diet. The known diets that can be used to achieve weight loss are called low-carbohydrate diet (LCHF), the Mediterranean diet (the Meditteranean diet), DASH and RESMENA diets, these diets are based on low-calorie foods.

Low-fat diets are associated with lower levels of a specific type of blood lipid (LDL cholesterol, low-density lipoprotein), while high-fat diets are associated with altered levels of other blood lipid (lower levels) (lower levels) Interestingly, only these changes are visible instantaneously, after a while the blood fats return to their previous values when the weight loss has reached its largest point and the individual begins to level out in the weight loss.50

In the studies where participants maintained a long-term weight loss, high protein intake, food with a low glycemic index (GI, a measure of how carbohydrates in food affected blood sugar level) and low fat intake were most effective. 50

Healthy diets
DASH dietA diet that emphasizes the importance of fruits, vegetables and whole grains, rather than refined grains. Fat-free or low-fat dairy products, fish. beans, nuts and vegetable oils are included, but foods with high levels of saturated fats, tropical oils (such as coconut oil), sugar-sweetened drinks and sweets should be limited.
The Mediterranean dietThe Mediterranean diet emphasizes that predominantly eats herbal foods, as fruits and vegetables, whole grains, legumes and nuts. Butter is replaced with healthy fats such as olive oil. Herbs and spices are used as flavorings instead of salt. Red meat is limited to a few times a month. Fish and chicken at least twice a week. Consumption of red wine in moderate amounts is optional.
RESMENA dietA variant of the Mediterranean diet that emphasizes the intake of fruits and/or vegetables with high levels of antioxidants and several smaller meals per day.
Low-carb high-fat diet (LCHF)LCHF emphasizes the importance of low levels of carbohydrates and dairy products with high levels of fat content. The diet recommends an increased intake of meat, eggs, root vegetables, nuts, berries and natural fat
(e.g. butter), as well as reduced consumption of pasta, rice, potatoes, beer, sugar, bread, and fruit.

Physical activity

Sedentary people and individuals with obesity are recommended to gradually increase aerobic physical activity, for example, fast walking 150 minutes per week. This has health benefits completely independent of weight loss. Some researchers believe that physical activity reduces the amount of the more unfavorable adipose tissue, i.e. abdominal obesity (visceral adipose tissue) and ectopic fat (ectopic fat).

To achieve prolonged weight loss, 60-90 minutes of training per day are required. Look Ahead is a well-known study that studied intensive lifestyle intervention (increased physical activity and reduced calorie intake) in individuals with type 2 diabetes and obesity, which showed that several risk factors for cardiovascular disease improved significantly already after the first year, then rising risk factors progressively as but after 4 years the risk factors were still longer than the initial situation.

The LOOK AHEAD study also investigated the effect of lifestyle intervention on cardiovascular diseases and death, the study demonstrated that increased physical activity and reduced calorie intake did not have an effect on overall survival after 8 years of follow-up.51

There is so far no proven difference between different types of training (aerobic vs resistance training vs high intensity vs low-intensity training) in terms of overall weight loss, but some believe that resistance training is better in obesity and overweight. The results of Look Ahead have been debated a lot and increased physical activity is still recommended.

Drug treatment for obesity

Medicines for the treatment of obesity are approved as an adjunct to dietary and exercise therapy in some countries; however, it is not approved for use during pregnancy or in younger individuals in several countries.40 The use of these medicines should be reserved for patients with severe obesity or high-risk obesity, i.e. BMI 27 kg/m2 with extensive comorbidity. 40

Drugs are most often prescribed to patients who previously tried to lose weight through exercise and improved diet. So far, there is no ideal medicine for obesity. Drugs available for obesity vary in different countries. The development of fatty medicines has been fraught with dangerous side effects and a number of preparations have been withdrawn from the market.

The majority of drugs identified against obesity have central stimulating mechanisms i.e. effects against the signaling system of the brain and act as a decrease in appetite by regulating adreno-, dopamine and serotonin receptors in the brain.

These mechanisms of action cause side effects in the form of psychiatric disorders, cardiovascular diseases and dependence development to the preparations. The first drug against obesity was launched in the 1930s, a drug called 2,4-Dinitrophenol (DNP) that caused weight loss by raising body temperature via increased activation of mitochondria in the body (cell power plants). The drug was withdrawn by the FDA in 1938 due to deaths.

In Sweden there is only one approved and discounted medicine for obesity, the substance is called Orlistat.

The drug works by binding to enzymes (proteins) in the gastrointestinal tract and prevents the enzymes from breaking down fat into smaller constituents in the intestine, resulting in reduced absorption of fats (free fatty acids and glycerol) into the blood. Studies have shown that 30% of the fat consumed is not absorbed by the body during ongoing treatment with Orlistat. The preparation is sold without a prescription in lower doses. The drug has a better effect for weight loss than diet and exercise but less effective than obesity surgery.

Mysimba is a medicine recently approved for weight loss in individuals with high BMI who have not achieved sufficient weight loss on diet and exercise. The drug is a combination drug that affects mainly a region of the brain called the nucleus arcuatus where it acts by inhibiting various receptors for signaling substances such as dopamine, norepinephrine and the mu-opioid receptor.

Mysimba also causes beneficial effects on most cardiovascular risk factors, although individuals who do not lose weight are at risk of developing an increase in blood pressure. There are several contraindications to treatment with Mysimba.

A substance called liraglutide used in the medicine Victoza against type 2 diabetes is also approved for the treatment of obesity and is then given in higher doses under the name Saxenda.

Saxenda has the same treatment indications as Mysimba but is a hormone called glucagon-like peptide-1 analog (GLP-1 analog) that regulates appetite by increasing sense of satiety as well as by increasing insulin secretion and reduced secretion of the hormone glucagon that lowers fasting glucose and sugar levels after food intake (post-prandial glucose). In addition, the substance has beneficial effects on overall survival and cardiovascular diseases.

Bariatric surgery (obesity surgery)

Bariatric surgery, also known as weight reduction surgery or obesity surgery, has been rapidly adopted as a treatment option for severe obesity and this has increased with the advent of laparoscopic operations (peephole surgery) leading to shorter interventions and lower risk of complications.

The treatment indication is BMI 40 kg/m2 or a BMI 35 kg/m2 with other co-morbidity, such as high blood pressure (hypertension) or impaired blood lipidemia (dyslipidemia).

Patients with pre-diabetes or newly onset diabetes can be operated with BMI 30-35 kg/m2.46 Bariatric surgery can also be performed in adolescents who are heavily overweight.

There are a variety of interventions and techniques that result in varying degrees of weight loss and each technique has its own risks and benefits that need to be carefully considered with the patient.45.46

The well-known Swedish Obese Subjects (SOS) study noted a significantly reduced risk of myocardial infarction and cancer in patients undergoing obesity surgery. Studies comparing surgical treatment against intensive medical treatment for obesity and type 2 diabetes have consistently shown greater improvements in blood sugar levels and obesity-related complications in the surgically treated group.

Several other diseases were also improved, such as type 2 diabetes and sleep apnea. During the follow-up period of the study, a slight return of body mass was noted but still lower than the baseline weight. Blood sugar levels are markedly improved in patients with obesity and type 2 diabetes.

Observational studies have observed that obesity surgery is superior to intensive drug therapy in order to reduce the risk of macrovascular and microvascular complications (myocardial infarction, stroke, renal failure, retinopathy and neuropathy).

The recurrence of type 2 diabetes in obesity surgery is probably due to weight loss, but there are also several hormones that are usually released from the gastrointestinal tract that rise after obesity surgery and have positive effects on metabolism, such as glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and Ghrelin.52

Some patients find it difficult to adapt to the huge changes in births and the type of food that patients have to consume after surgery. Lifelong replacement therapy with vitamins and minerals is necessary after the procedures.

Recurrent complications such as sudden and severe activation of the nervous system resulting in a drop in blood pressure and blood sugar drop immediately after food intake (gastric dumping syndrome), acid regurgitation (gastroesophageal reflux) and low blood sugar (hypoglycaemia) can be very troublesome and challenging to treat. Recovery weight long after surgery is also a problem.

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