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Keywords:

  • Obesity;
  • insulin resistance;
  • metabolic syndrome;
  • breathing abnormalities

Risks and diseases associated with increasing body weight (Table 1)

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References
Table 1.  Health risks associated with increasing Body Mass Index (BMI)
Metabolic syndrome30% of middle-aged people in developed countries have features of metabolic syndrome
Type 2 diabetes90% of type 2 diabetics have a body mass index (BMI) of >23 kg m−2
Hypertension5× risk in obesity
66% of hypertension is linked to excess weight
85% of hypertension is associated with a BMI >25 kg m−2
Coronary artery disease (CAD) and stroke3.6× risk of CAD for each unit change in BMI
Dyslipidaemia progressively develops as BMI increases from 21 kg m−2 with rise in small particle low-density lipoprotein
70% of obese women with hypertension have left ventricular hypertrophy
Obesity is a contributing factor to cardiac failure in >10% of patients
Overweight/obesity plus hypertension is associated with increased risk of ischaemic stroke
Respiratory effectsNeck circumference of >43 cm in men and >40.5 cm in women is associated with obstructive sleep apnoea, daytime somnolence and development of pulmonary hypertension
Cancers10% of all cancer deaths among non-smokers are related to obesity (30% of endometrial cancers)
Reproductive function6% of primary infertility in women is attributable to obesity
Impotency and infertility are frequently associated with obesity in men
Osteoarthritis (OA)Frequent association in the elderly with increasing body weight – risk of disability attributable to OA equal to heart disease and greater to any other medical disorder of the elderly
Liver and gall bladder diseaseOverweight and obesity associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH). 40% of NASH patients are obese; 20% have dyslipidaemia
3× risk of gall bladder disease in women with a BMI of >32 kg m−2; 7× risk if BMI of >45 kg m−2

The intra-abdominal visceral deposition of adipose tissue, which characterizes upper body – central – obesity (assessed by waist circumference and/or waist : hip ratio) is a major contributor to the development of hypertension, elevated plasma insulin concentrations and insulin resistance, hyperglycaemia and hyperlipidaemia (metabolic syndrome). The concept of the metabolic syndrome refers to the phenomenon of risk-factor clustering – a collection of metabolic traits occurring in the same individual with the clustering presumably reflecting a unifying underlying pathophysiology that requires a holistic approach to their management (5–7).

Many of the health risks associated with increasing body weight begin to appear in children and young people. Of great concern is the increasing prevalence of type 2 diabetes and associated medical complications in childhood (8–10). This early onset needs to be reflected by active management and research priorities to reduce the consequential health and economic burdens (11).

Identifying the genetic and environmental contributions to weight gain

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

Evidence from twin, adoption and family studies unequivocally indicates that inherited factors play a major role in the determination of inter-individual differences in fat mass. The identification of genetic variants influencing human fat mass is critical to obesity research. In general, mutations have been found in those rare children with extreme obesity and clear evidence for monogenic inheritance. Genetic studies in the more common forms of obesity have yet to have the same tangible success that has been seen with monogenic subtypes. Nevertheless, progress has been made in the identification of certain chromosomal loci containing genes conferring susceptibility to obesity. Body weight is determined by an interaction between genetic, environmental and psychosocial factors acting through the physiological regulation of energy intake and expenditure. Similarly, genetic, environmental and physiological factors are likely to determine the associated health risks. The genetic influences appear to operate through susceptibility genes, which may be expressed more frequently in certain ethnic groups (12). Such genes increase the risk of developing a characteristic but they are not essential for its expression or, by themselves, sufficient to explain the development of a disease. The differences in genetic susceptibility within a population are likely to determine those who are more likely to become obese and/or develop associated medical complications in any given set of environmental circumstances. Implicit to the susceptible gene hypothesis is the role of environmental factors that unmask latent tendencies to develop obesity and health risks.

A challenge for the future will be to identify the genetic and environmental contributions to weight gain, the intra-abdominal distribution of fat (central obesity) and also to health problems, paying attention to those at particular risk, including certain ethnic groups, susceptible families and the socially deprived. A further challenge will be to discover whether these factors operate through weight gain, independently or in combination.

The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

Obesity is characterized by elevated fasting plasma insulin and an exaggerated insulin response to an oral glucose load: a positive correlation is observed between increasing central obesity and measures of insulin resistance. Post-hepatic insulin delivery is increased in central obesity leading to more marked peripheral insulin concentrations that, in turn, lead to peripheral insulin resistance.

In both men and women, the lipolytic response to noradrenaline is more marked in abdominal than gluteal or femoral adipose tissue. Cortisol may also contribute to this enhanced lipolysis by further inhibiting the anti-lipolytic effect of insulin. Increased production of a fat-cell-specific protein called resistin by abdominal subcutaneous and omental adipose tissue is associated with decreased cellular insulin sensitivity. By contrast, there is an inverse relationship between adiponectin (an adipocyte-specific secretory protein) and adiposity and insulin sensitivity, with type 2 diabetes being characterized by low levels of adiponectin. Adiponectin is similar in structure to tumour necrosis factor-alpha (TNF-α), which paradoxically appears to be increased in abdominal adipose tissue. Increases in pro-inflammatory cytokines [interleukin 6, resistin, TNF-α and C-reactive protein (CRP)] reflect overproduction by the expanded adipose tissue mass (13,14). All of these factors contribute to the exaggerated release of free fatty acids (FFAs) from abdominal adipocytes into the portal system. FFAs have a deleterious effect on insulin uptake by the liver and contribute to the increased hepatic gluconeogenesis and hepatic glucose release observed in central obesity. Insulin insensitivity is not confined to adipocytes because the process is accentuated by skeletal muscle insulin resistance.

The contribution of metabolic alterations associated with weight gain to the development of health risks

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

The relationship between insulin resistance and hypertension is well established and is underpinned by several different mechanisms. Insulin is a vasodilator and has secondary effects on sodium reabsorption by the kidney. In the setting of insulin resistance, the vasodilatory effects of insulin can be lost but sodium reabsorption appears to be preserved. Insulin also increases sympathetic nervous system activity. Hyperinsulinaemia and insulin resistance are both significant correlates of a dyslipoproteinaemic state and contribute to the characteristic alterations of plasma lipid profile associated with obesity. Dyslipidaemia progressively develops with increasing abdominal fatness and body mass index (BMI). It is first noted at a BMI of 21 kg m−2 (2), when a rise in proatheromatous, dense, small-particle low-density lipoprotein (LDL) is seen. With elevated LDL concentrations, as well as high concentrations of triglycerides, coronary heart disease risk rises. The combined effect of saturated and trans-fatty acids on plasma lipids is amplified by the lack of n-3 long chain fatty acids, which have competitive effects on prostanoid synthesis, cellular function and thrombosis.

The effects of cytokines on peripheral tissues with increased intracellular lipids also lower cellular insulin sensitivity: the surge in lipids promotes proliferation of the vasa vasorum of the arterial media and apoptosis by the medial macrophages with a further release of cytokines. There is an additional complex relationship through an associated pro-inflammatory state and alterations in coagulability. A rise in blood viscosity is induced by the release of profibrinogen and plasminogen activator inhibitor 1 from adipocytes with a fall in plasminogen activator. These changes may explain the role of obesity as a promoter of intracellular inflammatory processes that result in arterial damage. Ethnic differences in CRP may explain some of the variation observed in insulin resistance across populations with comparable weight gain and associated medical complications. It is unclear whether tackling weight gain directly or treating the resulting pro-inflammatory state will have the greater health benefit.

The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

The effects of increased body fatness on cardiovascular function can be predicted. Total body oxygen consumption is increased because of an expanded lean tissue mass and metabolically active adipose tissue, and this is accompanied by an absolute increase in cardiac output. The total blood volume in obesity is increased in proportion to body weight. This increase in blood volume contributes to an increase in the left ventricular pre-load and an increase in resting cardiac output. The increased demand for cardiac output is achieved by an increase in stroke volume: an increase in stroke volume results from an increase in diastolic filling of the left ventricle. The volume expansion and increase in cardiac output lead to structural changes of the heart. The increase in left ventricular filling results in an increase in the left ventricular cavity dimension and an increase in wall stress. This thickening of the wall with dilatation results in eccentric hypertrophy. Left ventricular mass increases directly in proportion to BMI or the degree of overweight. In those subjects where systemic resistance is increased, the combination of hypertension and obesity results in an increase of ventricular wall dimensions disproportionate to the chamber radius that with time leads to concentric hypertrophy.

The cardiovascular adaptation to the increased intravascular volume of obesity may not completely restore normal haemodynamic function. Marked systolic dysfunction occurs when the ventricle can no longer adapt to volume overload. Dilatation of the left ventricle cavity radius leads to a decline in ventricular contractility. A combination of systolic and diastolic dysfunction progresses to heart failure (15).

An increased amount of fat in the chest wall and abdomen has an effect on the mechanical properties of the chest and leads to an alteration of respiratory excursion during inspiration and expiration, reduces lung volume and alters the pattern of ventilation to each region. Such changes are significantly exaggerated when an obese person lies down flat. The mass loading effect of fat requires an increased respiratory muscle force to overcome the excessive elastic recoil and an associated increase in the elastic work of breathing. The obesity-related changes in respiratory function are most important during sleep. Irregular respiration and occasional apnoeic episodes often occur in lean people during Rapid Eye Movement (REM) sleep, but obesity, with its influence on respiratory mechanics, increases their frequency and may result in severe hypoxia and resultant cardiac arrhythmias. Studies of obese men and women have demonstrated that the obstruction occurs in the larynx and is associated with loss of tone of the muscles controlling tongue movement. Relaxation of the genioglossus muscle allows the base of the tongue to fall back against the posterior pharyngeal wall, occluding the pharynx. This results in a temporary cessation of breathing (sleep apnoea) and associated transient fall in arterial oxygen saturation concentration – hypoxia. It is not uncommon to observe very low oxygen values during REM sleep in some obese subjects, even though their awake arterial gases are normal. Daytime somnolence may intervene, accompanied by persistent hypoxia and/or raised carbon dioxide (hypercapnia), pulmonary hypertension (superimposed on an increased circulatory volume) and right-sided cardiac failure. Such changes constitute the clinical manifestation of the obesity–hypoventilation syndrome, formerly known as the Pickwickian syndrome.

A number of groups have reported an increased risk of myocardial infarction and stroke associated with sleep apnoea. Snoring is a strong risk factor for sleep-related strokes, while sleep apnoea symptoms increase the risk of cerebral infarction. Importantly, body weight, independent of several traditional risk factors, is directly related to the development of congestive cardiac failure in the Framingham Heart Study, a clinical association not widely recognized.

The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

Changes in lifestyle are major contributors to the current epidemic of overweight and obesity. Energy-dense diets rich in fats and refined sugars promote weight gain, and high sugar and salt intakes also induce an increase in blood pressure. Traditionally, low-calorie diets (800–1500 kcal d−1), which incorporate various methods for restricting intake, have been recommended for weight management. The use of low-calorie diets with a treatment period beyond 6 months has been associated with a mean weight loss of ∼8%, although with longer use (3–4.5 years), this is reduced to ∼4%. Generally, these strategies aim to provide a macronutrient composition of 30–35% energy from fat, 50% from total carbohydrate and 10–15% from protein, thereby moving individuals towards national dietary guidelines.

Energy density is reduced by higher intake of vegetables and fruit, which the Dietary Approaches to Stop Hypertension (DASH) trial (16) showed also reduced blood pressure. Data from the DASH trial suggest that blood pressure can be lowered independently of weight change, especially in people with hypertension. Esposito and colleagues randomized 180 Italian men and women with the metabolic syndrome to a Mediterranean-style diet (food rich in mono- and polyunsaturated fat, fibre and a low ratio of omega-6 to omega-3 fatty acids) or to an ad lib diet, and followed them for 2 years (17). Subjects on the Mediterranean diet lost more weight but, even after accounting for this, there was a 39% reduction in the prevalence of the metabolic syndrome.

The American Diabetes Prevention Programme (18) and the Finnish diabetes prevention trial (19) used a low-fat diet in combination with physical activity (at least 150 min per week) and behavioural strategies to demonstrate the feasibility of sustaining modest weight loss (3–4 kg) over time (4 years), with an accompanying 58% reduction in the risk of developing type 2 diabetes.

Physical activity recommendations of 30 min of moderate activity on at least 5 days of the week are associated with improved fitness and protection from cardiovascular diseases (20). However, recent evidence highlights a requirement for 45–60 min per day to maintain lowered weight and prevent weight regain (21). Reduction in the time spent in sedentary behaviours (such as television watching) is an important strategy for increasing physical activity and energy expenditure in children and young people.

Research priorities

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References

Five areas for research into health risks associated with overweight and obesity have been identified. All of these areas will expand current scientific knowledge about the interrelated biological mechanisms and environmental factors that links weight gain to health risks. A priority is prevention of overweight and obesity in young people. Another priority is to test the effect of weight reduction by various dietary manipulations and increased physical activity in preventing and reducing health risks across the population. The pharmaceutical industry is actively investing in research into novel therapeutic agents for the management of established health risks and associated diseases. This will continue to require active collaboration across all spheres of academic laboratory and clinical research in the United Kingdom.

References

  1. Top of page
  2. Background
  3. Risks and diseases associated with increasing body weight ()
  4. Identifying the genetic and environmental contributions to weight gain
  5. The role of insulin resistance, cytokines and pro-inflammatory markers in the development of health risks
  6. The contribution of metabolic alterations associated with weight gain to the development of health risks
  7. The relationship between alterations in cardiac function, sleep-breathing abnormalities and the development of congestive cardiac failure in obesity
  8. The relative importance of weight loss, dietary composition and physical activity in reducing health risks associated with obesity
  9. Research priorities
  10. Conflict of Interest Statement
  11. References
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