NBS-nytt
03.08.2020
Obesity is a highly prevalent disease underlying several chronic diseases including Type 2 Diabetes (T2D), cardiovascular diseases (CVDs) and cancer, and is associated with increased risk of premature death. About 50% of people of European ancestry carry a set of non-coding mutations that is most strongly associated with obesity, although the underlying mechanisms have remained completely unknown.
Introduction to obesity
Obesity is defined as excessive fat accumulation that increases health risk1. The global prevalence of obesity has tripled since the 1970's2,3 with about 13% or 650 million affected adults worldwide today1. In Norway, 23% of the adult population were obese in 20184, which brings us among the top countries in Europe5, yet still behind the USA (35-40%)6.
The most widely used measure of body composition is the body mass index (BMI), which classifies obesity as BMI ? 30 kg/
m2 7 . For a person 1.80 m tall, this corresponds to a body weight of more than 97 kg. Although BMI is not the best measure of obesity on the individual level, as it does not take into account muscle mass, total fat mass, or more importantly, fat distribution, it is still a highly useful tool on the
population level.
Large epidemiological studies have above clearly shown that increases in BMI 30 is associated with an exponential increase in mortality risk8-10. Although the association is indisputable for obesity, it has been debated whether the same association also holds for overweight (BMI 2529.9)11. Clarifying this issue was important owing to the large number of overweight individuals that would potentially be at risk (about 2 billion)1. It is now known that when limiting the analysis to never-smokers, the increased mortality rate is apparent already in overweight subjects and this finding is even stronger in people 50 years of age8 (Figure 1). In this subgroup, the risk of premature death is 1.4 fold higher with overweight and 2-3 fold higher with obesity compared to normal weight8,10,12.
The increased risk of premature death with elevated BMI is mainly mediated by cardiovascular diseases like heart disease and stroke, which were the leading cause of death in 20121. However, elevated BMI is a also a well-known risk factor for several other noncommunicable and chronic diseases, including T2D, osteoarthritis, cancer, and microvascular diseases (retinopathy, nephropathy, These co-morbidities of obesity are major causes of disabilities and also place an enormous economic burden on the health care systems14. For example, overweight and obesity has been found to be responneuropathy)13. sible for 80% of cases of T2D15,16, and patients with T2D now accounts for 25% of the entire US health care budget17.
Adipose tissue dysfunction and insulin resistance
The mechanisms underlying the co-morbidities of obesity are complex, involving a range of metabolic, cellular and physiological pathways that converge on systemic insulin resistance and cardiovascular diseases, as reviewed elsewhere13. Central for these mechanisms is dysfunction of fat cells (herein termed adipocytes) which serve as master regulators of energy balance and play a major role in maintaining homeostasis of key nutrients, including lipids and glucose18.
In its simplest terms, obesity is caused by a chronic positive energy balance, where the energy intake and/or absorption outweighs the energy expenditure. Excess energy is converted into triacyl glycerides (TAG) and stored as lipid droplets in the adipocytes, providing a reservoir to buffer day-to-day variations in energy balance19. However, with a constant energy surplus, the demand for lipid-storing capacity increases, promoting a tremendous increase in both adipocyte size (hypertrophy) and numbers, resulting in enlargement of adipose tissue depots18.
The ability of adipocytes to increase in size depends on the plasticity of the extracellular matrix (ECM), a mesh of proteins that maintains the structure of the adipose depot. At some point, however, the enlarged adipocytes have no more room to expand, leading to a series of pathological effects, including ECM fibrosis, adipocyte lipid leakage, hypoxia, inflammation, cell death and changes in secreted adipokines, all promoting local and systemic insulin resistance13,18. The local insulin resistance in adipocytes promotes lipolysis, the hydrolysis of stored TAG to free fatty acids (FFAs) and glycerol which are released into the bloodstream and taken up by other organs including the liver and skeletal muscles13,20. In both organs, uptake of FFA promotes local insulin resistance, resulting in ectopic fat accumulation and elevated glucose output from the liver, as well as reduced glucose uptake in skeletal muscles, an unfortunate combination that elevates blood glucose (hyperglycemia)20. In response, pancreatic ?-cells secrete more insulin to achieve normoglycemia, until eventually ?-cells exhaustion occurs, leading to impaired insulin output and manifested hyperglycemia, a condition referred to as glucose intolerance or prediabetes. With progressively deteriorating ?-cell function, T2D will eventually develop21-23.
Genetic contribution to obesity
Environmental, genetic and epigenetic factors all play a role in obesity development and form complex interactions to modulate the energy balance13. For example, the per capita food availability and consumption has increased steadily for the last 70 years24, with a particular rise in energy-dense, processed and palatable foods, including sugar-sweetened beverages13,25. Coincidingly with increased energy intake,
Gå til medietObesity is defined as excessive fat accumulation that increases health risk1. The global prevalence of obesity has tripled since the 1970's2,3 with about 13% or 650 million affected adults worldwide today1. In Norway, 23% of the adult population were obese in 20184, which brings us among the top countries in Europe5, yet still behind the USA (35-40%)6.
The most widely used measure of body composition is the body mass index (BMI), which classifies obesity as BMI ? 30 kg/
m2 7 . For a person 1.80 m tall, this corresponds to a body weight of more than 97 kg. Although BMI is not the best measure of obesity on the individual level, as it does not take into account muscle mass, total fat mass, or more importantly, fat distribution, it is still a highly useful tool on the
population level.
Large epidemiological studies have above clearly shown that increases in BMI 30 is associated with an exponential increase in mortality risk8-10. Although the association is indisputable for obesity, it has been debated whether the same association also holds for overweight (BMI 2529.9)11. Clarifying this issue was important owing to the large number of overweight individuals that would potentially be at risk (about 2 billion)1. It is now known that when limiting the analysis to never-smokers, the increased mortality rate is apparent already in overweight subjects and this finding is even stronger in people 50 years of age8 (Figure 1). In this subgroup, the risk of premature death is 1.4 fold higher with overweight and 2-3 fold higher with obesity compared to normal weight8,10,12.
The increased risk of premature death with elevated BMI is mainly mediated by cardiovascular diseases like heart disease and stroke, which were the leading cause of death in 20121. However, elevated BMI is a also a well-known risk factor for several other noncommunicable and chronic diseases, including T2D, osteoarthritis, cancer, and microvascular diseases (retinopathy, nephropathy, These co-morbidities of obesity are major causes of disabilities and also place an enormous economic burden on the health care systems14. For example, overweight and obesity has been found to be responneuropathy)13. sible for 80% of cases of T2D15,16, and patients with T2D now accounts for 25% of the entire US health care budget17.
Adipose tissue dysfunction and insulin resistance
The mechanisms underlying the co-morbidities of obesity are complex, involving a range of metabolic, cellular and physiological pathways that converge on systemic insulin resistance and cardiovascular diseases, as reviewed elsewhere13. Central for these mechanisms is dysfunction of fat cells (herein termed adipocytes) which serve as master regulators of energy balance and play a major role in maintaining homeostasis of key nutrients, including lipids and glucose18.
In its simplest terms, obesity is caused by a chronic positive energy balance, where the energy intake and/or absorption outweighs the energy expenditure. Excess energy is converted into triacyl glycerides (TAG) and stored as lipid droplets in the adipocytes, providing a reservoir to buffer day-to-day variations in energy balance19. However, with a constant energy surplus, the demand for lipid-storing capacity increases, promoting a tremendous increase in both adipocyte size (hypertrophy) and numbers, resulting in enlargement of adipose tissue depots18.
The ability of adipocytes to increase in size depends on the plasticity of the extracellular matrix (ECM), a mesh of proteins that maintains the structure of the adipose depot. At some point, however, the enlarged adipocytes have no more room to expand, leading to a series of pathological effects, including ECM fibrosis, adipocyte lipid leakage, hypoxia, inflammation, cell death and changes in secreted adipokines, all promoting local and systemic insulin resistance13,18. The local insulin resistance in adipocytes promotes lipolysis, the hydrolysis of stored TAG to free fatty acids (FFAs) and glycerol which are released into the bloodstream and taken up by other organs including the liver and skeletal muscles13,20. In both organs, uptake of FFA promotes local insulin resistance, resulting in ectopic fat accumulation and elevated glucose output from the liver, as well as reduced glucose uptake in skeletal muscles, an unfortunate combination that elevates blood glucose (hyperglycemia)20. In response, pancreatic ?-cells secrete more insulin to achieve normoglycemia, until eventually ?-cells exhaustion occurs, leading to impaired insulin output and manifested hyperglycemia, a condition referred to as glucose intolerance or prediabetes. With progressively deteriorating ?-cell function, T2D will eventually develop21-23.
Genetic contribution to obesity
Environmental, genetic and epigenetic factors all play a role in obesity development and form complex interactions to modulate the energy balance13. For example, the per capita food availability and consumption has increased steadily for the last 70 years24, with a particular rise in energy-dense, processed and palatable foods, including sugar-sweetened beverages13,25. Coincidingly with increased energy intake,
